Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokine in vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40 micrograms/m2 and was ultimately escalated to 200 micrograms/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160 micrograms/m2 was defined as the MTD. At 160 micrograms/m2 peak serum levels occurred within 5-20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80 micrograms/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.
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PMID:A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion. 142 28

In a phase I study, the sequentially administered combination of recombinant human interleukin-3 (rhIL-3) and rhGM-CSF was compared with treatment with rhIL-3 alone in 15 patients with advanced tumors but normal hematopoiesis. Patients were initially treated with rhIL-3 for 15 days. After a treatment-free interval, the patients received a second 5-day cycle of rhIL-3 at an identical dosage, immediately followed by a 10-day course of rhGM-CSF, to assess the toxicity and biologic effects of this sequential rhIL-3/rhGM-CSF combination. rhIL-3 doses tested were 125, and 250 micrograms/m2, whereas rhGM-CSF was administered at a daily dosage of 250 micrograms/m2. Both cytokines were administered by subcutaneous (SC) bolus injection. rhIL-3/rhGM-CSF treatment was more effective than rhIL-3 but equally effective to each other in increasing peripheral leukocyte counts, especially neutrophilic and eosinophilic granulocyte counts. In contrast, both modes of cytokine therapy raised the platelet counts to the same degree. rhIL-3/GM-CSF treatment was more effective than rhIL-3 in increasing the number of circulating hematopoietic progenitor cells BFU-E and CFU-GM. High-dose rhIL-3, but not low-dose rhIL-3, was as effective as the rhIL-3/rhGM-CSF combinations in increasing the number of circulating CFU-GEMM. The increase in absolute neutrophil counts correlated with the increase in the number of circulating CFU-GM. Side effects, mainly fever, headache, flushing, and sweating, were generally mild, but in two patients the occurrence of chills, rigor, and dyspnea after initiation of GM-CSF treatment necessitated dose reduction and discontinuation, respectively. These results indicate that sequential treatment with rhIL-3 and rhGM-CSF is as effective as single-factor treatment with rhIL-3 in stimulating platelet counts, whereas the effect of combination therapy on neutrophil counts and circulating progenitor cells is superior.
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PMID:Sequential in vivo treatment with two recombinant human hematopoietic growth factors (interleukin-3 and granulocyte-macrophage colony-stimulating factor) as a new therapeutic modality to stimulate hematopoiesis: results of a phase I study. 158 11

To evaluate systemic cytokine and hypothalamic-pituitary-adrenal axis responses in migraine, we measured plasma levels of tumour necrosis factor, interleukin-1, adrenocorticotropic hormone, and cortisol, as well as body temperature during and between attacks in 20 migraine patients. We found no evidence of systemic rise of cytokines during migraine attacks. Plasma cortisol and adrenocorticotropic hormone responses were similar to those found to experimentally-induced pain in normal subjects, i.e. elevated cortisol and unchanged adrenocorticotropic hormone levels. Unexpectedly, body temperature tended to be lower during attacks.
Cephalalgia 1991 May
PMID:Plasma interleukin-1, tumour necrosis factor and hypothalamic-pituitary-adrenal axis responses during migraine attacks. 165 Feb 89

Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.
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PMID:Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly. 199 56

Interleukin-3 (IL-3) is a glycoprotein belonging to the hematopoietic growth factor family that in preclinical in vitro and in vivo studies has exhibited a multilineage activity. Phase I/II trials with recombinant human IL-3 (rhIL-3) expressed in yeast are being done in patients with advanced malignancies as well as in patients with bone marrow failure states. Subcutaneous administration of rhIL-3 at dosages between 30 and 500 micrograms/m2 for 15 consecutive days has resulted in a dose-dependent increase in platelet counts as well as in a substantial increase in the number of circulating neutrophils, eosinophils, monocytes, and lymphocytes in patients with advanced malignancies but normal hematopoiesis. Erythropoiesis is less stimulated with an increase in hemoglobin concentration only in a minority of patients. In patients with secondary hematopoietic failure due to prolonged chemo-/radiotherapy or bone marrow infiltration by tumor cells, treatment with rhIL-3 leads to a clinically significant restoration of hematopoiesis, especially of thrombopoiesis and granulopoiesis. rhIL-3 has also been shown to improve neutrophil and platelet counts in patients with myelodysplastic syndromes, while improvement of hematopoiesis is rarely observed in patients with severe aplastic anemia with the presently used treatment schedules. Adverse effects of rhIL-3 are minor at the clinically used dosages and include fever, bone pain, headache, and stiffness of the neck. Transient thrombocytopenia has been observed in a few patients with myelodysplastic syndrome or aplastic anemia treated at dosages of 250-500 micrograms/m2. rhIL-3 is a multilineage hematopoietic cytokine with promising effects on platelet and neutrophil counts and special usefulness in patients with secondary hematopoietic failure.
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PMID:Clinical effects of recombinant human interleukin-3. 204 66

A massive and self-limited release of tumor necrosis factor and interferon gamma was detected in the systemic circulation in 35 consecutive renal allograft recipients by specific radioimmunoassays very soon following the first injection of the monoclonal antibody OKT3 (anti-CD3). Peak serum TNF and IFN gamma levels were reached, respectively, at 1 and 4 hr following the first OKT3 injection. Abnormally high serum interleukin 2 levels were also observed 4 hr following the first OKT3 injection in a minority of patients (5 cases). OKT3 had no effect on interleukin 1 beta, interferon alpha, and granulocyte/macrophage colony stimulating factor serum levels, which in all patients remained within the normal range throughout the study. This selective OKT3-induced cytokine release, which only followed the first injection, was transient (i.e., lasting a few hours). It tightly paralleled the spontaneously reversible clinical syndrome characterized by high fever, headaches, and gastrointestinal symptoms that is invariably associated with the first OKT3 administration. Importantly, when administered in adequate dosages and with adequate timing, corticosteroids influenced both the cytokine release and the systemic reaction. Thus, the highest TNF, IFN gamma, and IL-2 serum levels were detected in patients who did not receive corticosteroids. Patients who received high-dose corticosteroids (1 g solumedrol bolus) concomitantly with the first OKT3 injection still had high TNF and IFN gamma levels. Conversely, when the same corticosteroid dose was injected 15-60 min prior to the first OKT3 injection, in all cases the increase of serum TNF and IFN gamma was significantly lower as compared with the above-described groups; IL-2 levels did not rise. These data offer a direct explanation for one major side effect of OKT3 and thus provide the basis for devising means to prevent its occurrence.
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PMID:In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. 210 79

Septic shock and invasive infection are diseases caused by humoral mediators of both exogenous and endogenous origin. The search for and identification of these factors has led to the discovery and molecular cloning of cachectin. This pyrogenic cytokine is identical to tumor necrosis factor (TNF) and, when released into the circulation, causes profound shock and multiple organ injury. Cachectin antibodies protect against the lethal effects of mice given endotoxin and baboons given E. coli, a result suggesting that this mediator is both necessary and sufficient to provoke septic shock. Cachectin is produced in humans after endotoxin infusion; the infusion of small doses of TNF is associated with fever, rigors, headache, and hypotension. Septicemic patients also produce cachectin, and during meningococcal infection, patients with the highest serum levels of cachectin die. Chronic cachectin production causes a potentially lethal syndrome of cachexia, anemia, and protein and lipid wasting. Future investigation is being directed toward the development of cachectin antibodies for use in treating the humorally mediated systemic complications of infectious disease.
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PMID:Cachectin: a hormone that triggers acute shock and chronic cachexia. 327 61

The hyperimmunoglobulinaemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent unpredictable febrile attacks with abdominal pain, joint involvement (arthralgias/arthritis), headache, skin lesions and a polyclonal elevation of serum IgD (> 100 U mL-1). Interferon-gamma (IFN-gamma) is a major proinflammatory cytokine which could play a role in the pathogenesis of the attacks. There is a need for parameters (if possible non-invasive) to monitor disease activity. A potential candidate is neopterin which is released by monocytes/macrophages when stimulated with IFN-gamma, excreted unchanged in urine, and appears to be an early and sensitive marker for activation of the immune system. We measured rectal body temperature, serum IFN-gamma, and urine neopterin in 10 hyper-IgD patients both during and between attacks. The body temperature rose to a mean of 38.9 degrees C on the first day of the attack and normalized within 5 days. Serum IFN-gamma during the first day of the attack was 2.98 IU mL-1 and was significantly lower during remissions. The urine neopterin excretion was 268 +/- 170 mumol mol-1 creatinine between attacks and was significantly increased to 638 +/- 275 mumol mol-1 creatinine on the first day of symptoms. Maximal urine neopterin values were reached on the fourth day of the attack (1051 +/- 387 mumol mol-1 creatinine) and excretion gradually declined and attained values below 400 mumol mol-1 creatinine after 9 days. There was a good correlation between serum IFN-gamma and urine neopterin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma and urine neopterin in attacks of the hyperimmunoglobulinaemia D and periodic fever syndrome. 749 43

A pilot study was devised to assess tolerance of combined administration of interleukin-3 (IL-3) and granulocyte-colony stimulating factor (G-CSF) given after chemotherapy to mobilize peripheral blood progenitors cells (PBPC). Eight patients with advanced malignancies received 1 week courses of both IL-3 and G-CSF in one of three schedules: simultaneous 7 days administration (3 patients), sequential administration (3 patients) or partial (3 days) overlap of the two growth factors (2 patients). IL-3 (7.5 micrograms/kg/day) and G-CSF (5 micrograms/kg/day for the simultaneous schedule and 12 micrograms/kg/day for the partial overlapping and sequential schedules) were administered subcutaneously. Side-effects during cytokine administration included WHO grade I-II fever in 6 of 8 patients, flu-like symptoms (including myalgias and arthralgias) in 4 of 8, WHO grade I-II headache in 2 of 8 and WHO grade II nausea and vomiting in 1 of 8. Overall, side-effects appeared similar during combined administration of IL-3 and G-CSF to those observed during administration of IL-3 alone. No fever was observed when G-CSF was administered alone. Two leukaphereses were performed following the treatment with cytokines. Only the seven patients who received cytokines following chemotherapy were analyzed for PBPC mobilization. The median collection of CFU-GM/kg per patient in the seven analyzed patients was 1.3 x 10(5) (range 5.7 x 10(2)-3.6 x 10(5)). In two patients, a second cycle of mobilization with either granulocyte macrophage-colony stimulating factor (GM-CSF) or G-CSF was administered to allow safe engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tolerance of sequential or simultaneous administration of IL-3 and G-CSF in improving peripheral blood stem cells harvesting following multi-agent chemotherapy: a pilot study. 751 99

Recombinant human interleukin-6 (IL-6) has previously been shown to increase platelet counts in normal and sublethally irradiated mice, dogs, and primates. To assess its tolerance and efficacy in clinical use, we performed a randomized phase Ib study in patients with ovarian carcinoma. IL-6 was administered during an initial 7-day cycle before any chemotherapy. Beginning 7 days later, six cycles of chemotherapy containing carboplatin were administered every 3 weeks. During chemotherapy cycles 2 to 6, IL-6 was administered from day 4 through day 17 at escalating dose levels from 0.5 to 10 micrograms/kg/d. At each level, three patients received IL-6 and one patient received a placebo. During the prechemotherapy cycle of IL-6, a dose-dependent increase in platelet count was observed from day 12 to 15 and was maximal on day 15 (r = .77; P < .01). The median ploidy of bone marrow megakaryocytes shifted from 16 N to 32 N after 7 days of the initial prechemotherapy IL-6 administration. Dose-dependent increases in C-reactive protein (CRP) and fibrinogen levels were observed on day 8 (P < .0001 for both). A significant decrease in hemoglobin level occured rapidly after initiation of IL-6 therapy and was maximal on day 8 (P < .001). When given after chemotherapy, IL-6 accelerated platelet recovery after chemotherapy cycles 2 to 6. Postponements of scheduled chemotherapy due to thrombocytopenia were less frequent in patients treated with IL-6. No difference in either neutrophils or peripheral blood progenitor assays was observed during or after IL-6 treatment. Toxicity of IL-6 appeared mild and was not dose-limiting up to 10 micrograms/kg/d. Systemic symptoms such as fever, headache, and myalgia were the main side effects and were easily relieved by acetaminophen administration. No biologic toxicity was observed. The data indicate that IL-6 is a well-tolerated cytokine and capable of accelerating platelet recovery in patients receiving chemotherapy.
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PMID:Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo-controlled, randomized phase Ib study. 753 10


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