Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Immunological effects of recombinant interferon alfa-2a in patients with disseminated melanoma. 348 11

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells generated from autologous lymphocytes has produced significant tumor regressions in patients with advanced cancer. In the current study, we reviewed the hematologic effects associated with this therapy in our initial 42 patients. Eighty-eight percent of the treated patients developed anemia that required greater than or equal to 4 units of red cell transfusions, and 43% received at least 8 units. Only a blood loss of 2 to 3 units could be attributed to repeated phlebotomy, cytophereses, and hemodilution. IL-2 administration also resulted in thrombocytopenia as well as lymphopenia and eosinophilia. Forty-three percent of patients developed platelet counts of less than or equal to 50,000/microL, and 36% of the total group required platelet transfusions. Mild neutropenia and a rebound lymphocytosis followed discontinuation of IL-2 treatment. To explore the possible mechanisms for these hematologic effects, standard hematopoietic colony assays were conducted on serial blood samples from five patients. IL-2 produced a significant decline in circulating erythroid (BFU-E) and granulocytic/macrophage (CFU-C) progenitors, which rebounded after the discontinuation of IL-2 therapy. Infusion of IL-2 also resulted in measurable serum levels of gamma-interferon. Some of the hematologic effects of immunotherapy with LAK cells and IL-2 may be the result of IL-2-mediated suppression of hematopoiesis.
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PMID:Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2 in cancer patients. 349 2

This paper reports information on the levels of interferon (IFN) in the blood serum of dairy calves given 10(6) U of bacteria-derived bovine alpha I1 interferon per kg of body weight by intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.), and intranasal (i.n.) routes. Highest levels (10,000 U/ml) in the vesicular stomatitis viral assay system were obtained after i.v. administration and occurred within 30 min of a dose; levels rapidly declined thereafter to a low of 200 to 300 U/ml by 24 h. Serum inhibitory activity against vesicular stomatitis virus in this range is sometimes found in normal dairy calves. Levels after i.m. and s.c. administration were similar: a plateau of 1,000 to 2,000 U/ml between 2 and 8 h after a treatment with a decline to 200 to 300 U/ml by 24 h. Serum IFN was not detected after i.n. dosing or in the control group given physiological buffered saline by the i.m. route. A transitory moderate febrile response, but no other clinical adverse effects, was noted after the first intramuscular dose of IFN, but not after subsequent i.m. doses. No clinical signs were noted after i.v., s.c., or i.n. dosing or in the control calves given physiological buffered saline intramuscularly. After i.v., s.c., and i.m. administration of IFN, leukopenia, neutropenia, and lymphocytopenia were observed; these were most prominent within the first 24 h after the initial dose of IFN.
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PMID:Levels of interferon in blood serum and toxicity studies of bacteria-derived bovine alpha I1 interferon in dairy calves. 374 21

Studies were initiated to assess the response of patients with disseminated melanoma to recombinant alpha interferon (rIFN-alpha A) and to monitor effects of rIFN-alpha A on several tests of immune function. Twenty patients were treated with rIFN-alpha A given by i.m. injection in escalating doses from 15 to 50 X 10(6) um-2. The responses of two patients were considered unevaluable. Of the remainder there was complete remission of tumour in two and stable disease in two. Subsequent progression of tumour in one of the latter patients coincided with development of antibodies to IFN. Side effects (usually fatigue) were dose rate limiting in 11 patients. Laboratory tests on samples taken 6 hours after rIFN-alpha A indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity particularly against K562 target cells. Longer term changes measured in samples taken 2 days after the previous rIFN-alpha A injections consisted of neutropenia and an increase in the T4/T8 ratio due mainly to a relative increase in OKT4 positive T cells compared to OKT8 positive T cells. NK activity against the K562 target cell increased in most patients during the first week of treatment and then returned to below or near pretreatment levels thereafter against the K562 target cell. This contrasted with NK activity against the melanoma target cell which showed a more gradual increase over the duration of the treatment in 6 patients. The latter correlated with an increase in mitogen stimulated IL 2 production from their blood lymphocytes and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. These results confirm the activity of rIFN-alpha A against melanoma in certain patients. They suggest that further studies are needed to select patients who may respond to rIFN-alpha A and to optimize treatment regimens. Tests of IL 2 production and LAK activity may assisted in achieving these objectives.
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PMID:Effects of recombinant leukocyte interferon (rIFN-alpha A) on tumour growth and immune responses in patients with metastatic melanoma. 387 53

Natural killer (NK) cell activity was measured by a 51Cr-release assay using K562 target cells in 12 neutropenic children. NK cell activity was depressed in four patients who had childhood chronic neutropenia with abnormal neutrophil morphology and chemotaxis. The percentage of lysis at a 40:1 effector-target ratio was 28.4% to 42.1% (P less than .001) of the normal lymphocyte value during the study period (32 to 40 months). NK cell activity was normal in the other eight children with chronic neutropenia without any of these neutrophil abnormalities: lazy leukocyte syndrome, Shwachman syndrome, or dysgammaglobulinemia type I with neutrophil defects. NK cell activity of the four patients was depressed at 5:1 to 40:1 effector-target ratios. The NK cells responded to in vitro interferon (IFN)-alpha and interleukin 2, as did normal lymphocytes, but the activated levels were still lower than those of normal lymphocytes (P less than .01). Because NK cells kill a target through recognition, binding, killing, and detaching, and they repeat this lytic sequence (ie, recycling), the localization of the NK cell defect was further analyzed in the four patients using both 51Cr-release and single cell-in-agarose assays. The patients' NK cells were normal in recognizing, binding, and killing a target but were defective in recycling; the estimated maximum recycling capacity (MRC) values in a four-hour assay were 1.8 to 2.4 (P less than .01), as compared with the normal lymphocyte value of 5.5 +/- 0.6 (mean +/- SD). The stimulation of the effector cells with 1,000 U/mL IFN-alpha did not significantly increase the estimated MRC. These results demonstrate that NK cells are defective in recycling in some type of childhood chronic neutropenia with abnormal neutrophil morphology and chemotaxis. The NK cell deficiency is of clinical interest in terms of its relationship to the recurrent infections, development of malignancy, and dysgranulopoiesis in the disorder.
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PMID:Impaired natural killer cell recycling in childhood chronic neutropenia with morphological abnormalities and defective chemotaxis of neutrophils. 387 72

Monocyte function in rhesus monkeys with simian acquired immune deficiency syndrome (SAIDS) was compared with that in age-matched normal juvenile rhesus monkeys. The functional tests were 1) chemotaxis, 2) phagocytosis of opsonized Candida albicans, 3) killing and/or growth inhibition of Candida albicans, 4) generation of respiratory burst, and 5) monocyte-derived macrophage response (morphology and/or respiratory burst) to stimulating agents such as lymphokines, gamma interferon, endotoxin, and phorbol myristate acetate. The monkeys tested had either clinical SAIDS (alive with lymphadenopathy, splenomegaly, and lymphopenia or neutropenia) or had terminal SAIDS (moribund due to the disease). Responses of monocytes from 14 monkeys with clinical SAIDS were indistinguishable from those of 9 normal juvenile rhesus monkeys, whereas monocytes from 3 monkeys with terminal SAIDS had enhanced phagocytosis and respiratory burst capacity. Chemotaxis, candidacidal/stasis activity, and response to stimulating agents were normal in these terminal cases. Plasma from the SAIDS monkeys was as capable of opsonizing yeasts and of being able to generate chemotactic factors by endotoxin as was control plasma. SAIDS retrovirus (SRV) was detected by co-cultivation of pure monocyte-derived macrophage cultures with Raji cells, an indicator cell line which forms syncytia in the presence of SRV. Four terminal SAIDS cases and one late-stage clinical SAIDS case were virus-positive when the number of macrophages in the cultures ranged from less than 50 to about 500. Terminal SAIDS monocyte-derived macrophages in culture as long as 17 days produced SRV. These data show that in monkeys with SAIDS the major effector functions of monocytes and macrophages involved in host defense are intact (even up until death). Additionally, some of the monocytes are productively infected, and these infected monocytes are viable and adherent in culture.
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PMID:Monocyte function in rhesus monkeys with simian acquired immune deficiency syndrome. 390 21

Nine patients with chronic type B hepatitis were entered into a preliminary study of recombinant, human alpha-interferon therapy. Patients received one to four courses of interferon, each consisting of a fixed dose of 18, 36, 50, 68, or 100 million units given three times a week for 2 wk. Side effects including fever, chills, fatigue, myalgias, headache, and neutropenia were common and especially severe with higher doses. Serum hepatitis B virus DNA polymerase activity fell during therapy to 15%-30% of the pretreatment levels irrespective of interferon dose, but rose to the initial level by 10 days after the course ended. During follow-up, 2 patients had a sustained clinical remission in which hepatitis B virus DNA, DNA polymerase, and hepatitis B e antigen disappeared from serum and amino-transferase activities fell to normal. One patient became hepatitis B surface antigen negative. We conclude that higher doses (50 and 68 million units) of interferon have greater side effects than lower doses (18 and 36 million units), without having any greater antiviral efficacy. Further studies should be directed at therapy with lower doses given over longer periods.
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PMID:Pilot study of recombinant human alpha-interferon for chronic type B hepatitis. 394 Feb 41

Seventeen patients with hairy cell leukemia (HCL) were treated with low doses of recombinant alpha interferon (IFN) for over 4 months. Marked improvement was observed in peripheral blood and bone marrow in 15 of 17 patients. Comparison of pretreatment values and hemograms obtained after 4 months of treatment showed a marked decrease in circulating hairy cells (P less than .01), a decrease in the number of lymphocytes (P less than .01), a rise in the number of platelets (P less than .05), granulocytes (P less than .05), and monocytes (P less than .01), and a rise in the hemoglobin level (P less than .01). Transient reduction in the number of granulocytes was noted during the first month. Correction of thrombocytopenia often appeared within 2 months and usually preceded improvement of anemia, monocytopenia, and neutropenia. Bone marrow biopsy specimens were taken before treatment and 2, 4, and 7 months after its initiation. The volumes occupied by hairy cells, cells of the myeloid lines, and adipocytes were studied by stereological analysis of semithin sections. Decrease in the volume occupied by hairy cells was seen after 4 months of treatment (P less than .01), and the volume continued to decrease at the seventh month (P less than .05). Hairy cells were no longer detected on bone marrow biopsies of 4 of 17 patients by the fourth month and in 3 of 8 additional patients by the seventh month. A rise in the volume occupied by normal myeloid cells was visible by the second month of treatment (P less than .01). Nevertheless, the volume occupied by granulocytes remained lower than in the normal controls (P less than .01). After an initial increase during the first 2 months of treatment (P less than .01), the overall cellularity remained unchanged at 4 months and decreased significantly (P less than .05) at 7 months. Except for biopsies at 2 months, mean cellularity was below that of control biopsies (P less than .01).
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PMID:Treatment of hairy cell leukemia with recombinant alpha interferon: I. Quantitative study of bone marrow changes during the first months of treatment. 394 48

Three patients had leukocytosis of large granular lymphocytes and chronic neutropenia. Clonal chromosomal abnormalities (trisomy 8 and trisomy 14) and lymphocytic infiltration of splenic red pulp, hepatic sinusoids, and bone marrow indicated the neoplastic nature of the large granular lymphocytes. Demonstration of a T3+, T8+, HNK-1 + phenotype and low natural killer cell activity that was augmented by interferon treatment showed the leukemic cells to be immature natural killer cells. Multiple autoantibodies were present and included rheumatoid factor and antinuclear, antineutrophil, antiplatelet, and antierythrocyte antibodies, suggesting a defect of B-cell immunoregulation. In addition, in-vitro studies showed impaired suppression of immunoglobulin biosynthesis by abnormal cells from one patient. Antineutrophil antibodies and absence of direct cell-mediated inhibition of granulocyte-macrophage colony formation supported a humoral immune mechanism for the neutropenia. In these patients the syndrome of splenomegaly, multiple autoantibodies with neutropenia, and lymphocytosis of large granular lymphocytes is due to a neoplastic proliferation of immature natural killer cells.
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PMID:Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. 396 54

In two phase I-II trials, 33 patients were given recombinant interferon alpha-2 daily at dosages of 3, 10, 30, 50, or 100 MU/d for up to 4 weeks by intramuscular or intravenous routes. Dose-limiting toxicities, including neutropenia, elevated hepatocellular enzyme levels, fatigue, and disturbed mentation, correlated with differing serum pharmacokinetics of interferon in the two trials. In the intramuscular study, dose-limiting toxicity occurred at all dosages greater than 10 MU/d, at a median of 6 to 9 days of treatment. In the intravenous dose-study, limiting toxicity was seen only at dosages of 100 MU/d, at a median of day 8. Twenty-three patients had metastatic melanoma and 4 had objective partial or complete responses at dosages of 10 to 50 MU/d in the first month. Two patients with complete responses are free of tumor after 2.5 years of follow-up. A fifth patient had delayed complete regression, requiring 1 year to achieve maximum response, but remains free of disease at 26 months since entry to the trial. Interferon had antitumor activity against melanoma by both routes tested, at dosages of 10 to 50 MU/d.
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PMID:Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma and other cancers. 400 87


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