Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:A phase I trial of recombinant human interferon-gamma in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). 254 86

The molecular mechanisms which govern the biosynthesis and secretion of the various T cell-derived lymphokines are poorly understood at this time, in spite of their tremendous importance to the control of the mammalian immune system. Here we provide compelling evidence that production of the murine T cell growth factors interleukin (IL) 2 and IL4 are differentially regulated by glucocorticoid (GCS) hormones. Under conditions where IL2 production is reduced by GCS hormones, IL4 production is increased. In vivo, this effect on T cell production of growth factors is manifest at low GCS concentrations that are well within physiologic ranges. In vitro, splenocytes isolated from antigen-stimulated donors, as well as antigen-specific cloned T cell lines, undergo alterations in their capacity to secrete T cell growth factors when stimulated with antigens in the presence of GCS. Responses normally dominated by IL2 are dramatically shifted to a condition where IL4 represents the major species of T cell growth factor produced. Similar changes in the pattern of T cell growth factor production are observed following short pulses with low-dose GCS in vitro, and the steroid-induced depression in IL2 production can be reversed and/or inhibited by treatment with the potent steroid antagonist RU486. Our results imply that GCS hormones, presumably through their capacity to activate a specified family of ligand-dependent transcriptional regulatory proteins (steroid hormone receptors), function to control the pattern of lymphokines produced by activated T cells. Steroid-mediated regulation of lymphokine gene expression could serve to dictate the types of immune effector mechanisms which can be initiated subsequent to antigen exposure.
 ...
PMID:Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. 260 41

The administration of interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells can mediate the regression of cancer. Treatment with IL-2 is associated with significant cardiorespiratory effects, as well as a leaky capillary syndrome requiring careful fluid management. A mild reversible depression of cardiac function is also associated with IL-2 treatment. All patients treated with recombinant IL-2 alone, with transfer of LAK cells, or with cyclophosphamide between December 1984 and September 1987 (total of 423 treatment courses in 317 total patients) were evaluated as to the development of significant cardiorespiratory toxicity. Of the 423 treatment courses, only 1.8% were associated with severe peripheral edema and only 2.8% and 3.1% respectively, were associated with significant ascites or pleural effusions. Thirty-nine of 423 patients (9.2%) had severe respiratory distress and 27 patients required intubation (6.4%). Cardiovascular effects included tachycardia and hypotension requiring vasopressor administration in 65% and intravenous (IV) fluid administration. Weight gain greater than or equal to 10% of body weight was noted in 32% of the 423 patients. Arrhythmias were primarily supraventricular (9.7%) and responded well to conventional medical treatments. Angina or ischemic changes were noted in 2.6% of patients and myocardial infarction in 1.2%. IL-2 caused peripheral vasodilation, with a significant decrease in peripheral vascular resistance (2,254 +/- 398 v 1,303 +/- 351 dyne.s.cm-5, P less than .0001), and an increase in heart rate (66.2 +/- 10 v 104.3 +/- 9.6 beats/min, P less than .0001). There was also evidence of mild cardiac dysfunction, with a significant decrease in the left ventricular stroke work (LVSW) index (P less than .0001) and ejection fraction (LVEF) (from 58% +/- 10% to 52% +/- 9%, P less than .03). A repeat LVEF performed after 1 to 3 months, had returned to baseline values (60% +/- 10%). A mean 64% increase in the rate of disappearance of radioactive iodine (125I) albumin (P less than .05) consistent with the development of a leaky capillary syndrome was noted. Patients with underlying cardiorespiratory diseases may be at greater risk during IL-2 administration and should not be selected to undergo this treatment.
 ...
PMID:Cardiorespiratory effects of immunotherapy with interleukin-2. 278 38

Cellular immune reactivity was investigated in 49 newly diagnosed children with Wilms' tumor and compared to age-matched control. The level of total T (T4 degrees) and B lymphocytes was normal while the relative number of T lymphocytes with high affinity receptors for sheep erythrocytes (T29 degrees) was significantly decreased in the patients studied. The lymphocyte response to PHA in vitro was diminished but PHA-induced lymphokine production was not altered. The depression of T29 degrees level and lymphocyte reactivity to PHA was associated with high grade tumor rather than with the clinical stage. Lymphocytes of 42-47% patients reacted with autochthonous and allogeneic KCl tumor extracts in the migration inhibition test and the degree of reactivity was related to the histological differentiation of the tumor.
 ...
PMID:Immunological reactivity in children with Wilms' tumor. 302 Apr 56

Concentrations of hydrocortisone as low as 0.08 microgram/ml significantly reduced the yields of gamma-interferon (IFN-gamma) when phytohemagglutinin (PHA) or concanavalin A (ConA) were used as inducers; however, when staphylococcal enterotoxin A was utilized, higher concentrations (5.0 micrograms/ml) were required to achieve the same effect. Yields of interleukin-2 (IL-2) and lymphotoxin were also found to be sensitive to the effects of the steroids, but expressions of TAC antigen was not generally affected by these agents. In contrast to the effects of steroids on cell proliferation, lymphokine production remained suppressed after steroid withdrawal. Hydrocortisone appeared to influence the concentrations of cyclic nucleotides following lectin stimulation, but attempts to correct these alterations or to add exogenous IL-2 failed to restore lymphokine production to normal levels. Addition of the calcium ionophore A23187 partially restored IFN-gamma production. We conclude that the effects of corticosteroids on the yields of lymphokines, including IFN-gamma, are profound. The depression of lymphokine production appears to be associated with a number of alterations in the cell, including depression of protein synthesis, alterations in cyclic nucleotides, and diminution of the production of cofactors necessary for IFN-gamma production. Enhancement of the flux of calcium into the cell may restore some of the ability to produce IFN-gamma.
 ...
PMID:The effect of hydrocortisone on the production of gamma-interferon and other lymphokines by human peripheral blood mononuclear cells. 302 73

Interleukin 2 (IL-2) therapies have antitumor activities against several neoplasms. In vitro these activities are enhanced by beta-interferon (IFN-beta). Therefore, we initiated a Phase I trial with a combination of IL-2 and IFN-beta three times weekly. The IFN-beta was administered i.v. Initially, the IL-2 was administered s.c. However, neutralizing antibody to the IL-2 developed in five patients, and the route of administration of the IL-2 was changed to i.v. Forty-seven patients were entered on the study. The maximum tolerated doses for the combination given i.v. were 5 x 10(6) units/m2 of IL-2 and 10 x 10(6) units/m2 of IFN-beta. Dose-limiting toxicities were profound fatigue/decreased performance status, anorexia/weight loss, depression, and arthralgias. Hypotension, exfoliative skin rash, thrombocytopenia, diarrhea, temperature greater than 40.6 degrees C, and peripheral edema were rarely dose limiting. Thirty-two patients were evaluable for response. After 4 weeks of treatment, 21 patients had stable disease, three patients had a minor response, and one patient had a partial response. Significant lymphokine-activated killer cell (LAK) activity was seen in seven patients (22%) and required 5 x 10(6) units/m2 of IL-2. Those who had progressive disease had significantly less LAK activity than those with either stable disease or a response. This therapy also induced more than 60 units/ml of endogenous gamma-interferon 4 h after the i.v. IL-2 administration. This study demonstrates that (a) intermittent i.v. bolus IL-2 therapy can generate LAK activity, (b) LAK activity may be associated with an antitumor response, (c) significant levels of gamma-interferon are induced by this therapy, and (d) IL-2 and IFN-beta given three times weekly i.v. is both tolerable and biologically active. The recommended Phase II dose is 5 x 10(6) units/m2 of IL-2 plus 6 x 10(6) units/m2 of IFN-beta.
 ...
PMID:A phase I study of recombinant interleukin 2 plus recombinant beta-interferon. 313 24

Beta-2-adrenergic agonists are often employed in the treatment of acute bronchostenosis. Following our recent investigations into the influence of some drugs (cromolyn, ketotifen, theophylline) on the immune response, in this study we analyzed the in vitro effects of fenoterol (beta-2-adrenergic agonist) on the immune response. The mitogen-(PHA)-induced proliferation of peripheral mononuclear cells (PMNC), the PMNC proliferation induced by anti-T3 and anti-T11 monoclonal antibodies (MAbs), the PHA-induced lymphokine--interleukin 2 (IL-2) and interferon-gamma (IFN-gamma)--production were studied in ten healthy volunteers. Since the plasmatic peak of fenoterol following a single inhalation of 200 micrograms is about 20 ng/ml, in the experiments herein reported the drug was tested in the cultures at concentrations lower, equal and higher than the plasmatic peak: respectively, 2, 20 and 200 ng/ml. Furthermore, for a more detailed study of T-lymphocyte activities, we also evaluated the effect of fenoterol on T-cell clone proliferation. Our results, which reveal no effects of fenoterol on the studied immunological parameters, acquire relevance when related to our previous reports showing a depression of the immunological response exerted by theophylline and ketotifen.
 ...
PMID:Fenoterol effects on the in vitro immune response. 317 57

Cytotoxic activities of regional lymph node lymphocytes (RLNL) and peripheral blood lymphocytes (PBL) of 49 primary lung cancer patients who were subjected to surgical resection were examined by 4 h 51Cr release assay. PBL showed significantly lower cytotoxicity against autologous tumor cells than against K562 and QG-56. On the other hand, RLNL exhibited the same level of cytotoxicity against autologous tumor cells as PBL, although the cytotoxicities against K562 and QG-56 were low. Cytotoxicity of RLNL against autologous tumor cells exhibited a significant degree of depression with the advance of stage, T and N factors. Cytotoxicity of PBL did not significantly change as the stage progressed. When both PBL and RLNL were cultured with purified interleukin-2 (p-IL2) in vitro, their cytotoxic activities were markedly augmented and the cytotoxicities could not be diminished by the treatment with anti-Leu-7 + anti-Leu-11b + C'. These facts indicate that the augmented cytotoxicity may be due to lymphokine activated killer (LAK) cells.
 ...
PMID:Antitumor activity of regional lymph node lymphocytes in patients with lung cancer. 326 Jun 43

The depression of cell-mediated immunity (CMI) was determined in patients with ovarian and breast carcinomas by lymphokine production under Con-A-stimulation (migration inhibitory factor), T-lymphocyte-transformation test under PHA-stimulation and with a skin reactivity test with a viscum album extract (Plenosol, Dr. Madaus, Cologne, FRG). The results show a good correlation between the different types of CMI function tests. The cytostatics have a depressive effect on CMI more through a cumulative effect than through the actual concentration. Some of the patients with chronic rheumatism who were not treated were anergic, and that also had an influence on the therapy.
 ...
PMID:Assay of the cell-mediated immunity in patients with malignant and non-malignant diseases. 330 58

Twenty patients with disseminated melanoma were treated with interferon alfa-2a, given by intramuscular (IM) injection three times a week in escalating doses from 15 to 50 X 10(6) U/m2. Of 18 patients considered evaluable, two had complete remission and in two others the disease was stabilized. Laboratory tests 6 hours after injection of interferon alfa-2a indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity. Sequential changes (measured before injection of interferon alfa-2a on days 3, 10, and 31) consisted of neutropenia, thrombocytopenia, and a slight increase in OKT4 positive T cells compared with OKT8 positive T cells. NK activity against the K562 target cells was increased in most patients during the first week of treatment, returning to near or below pretreatment levels thereafter. This response contrasted with a delayed increase against melanoma target cells in 10 patients. The latter correlated with an increase in mitogen-stimulated interleukin-2 (IL2) production, and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. Changes in cortisol levels may explain some effects on the immune system, such as depression of IL2 and immunoglobulin production in vitro, and the differences noted in clinical responses during the present study compared with those observed with interferon alfa-2b given by intravenous (IV) injection in 5-day cycles. These results suggest that interferon alfa-2a has antitumor activity in certain melanoma patients, in particular those with metastases to pulmonary or subcutaneous sites. Assays of IL2 production and LAK activity may assist in the selection of patients who respond to interferon alfa-2a and help to optimize treatment regimens.
 ...
PMID:Immunological effects of recombinant interferon alfa-2a in patients with disseminated melanoma. 348 11


<< Previous 1 2 3 4 5 Next >>