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Biomedical subjects

J U Gutterman

Publications and source records attributed to J U Gutterman.

At least 181 records · Page 10Linked to original sources
PubMed1985

Impaired in vitro interferon, blastogenic, and natural killer cell responses to viral stimulation in acquired immune deficiency syndrome.

The in vitro immune response to herpes simplex virus (HSV), type 1, strain 539, HSV type 2, strain 316D, and cytomegalovirus was studied in 20 patients (14 with acquired immune deficiency syndrome, four with the acquired immune deficiency syndrome-related symptom complex, and two sexually active asymptomatic homosexuals) and 18 heterosexual healthy controls. Peripheral blood mononuclear cells were cultured with 2 X 10(5) plaque-forming units of heat-inactivated viruses, their lymphocyte blastogenic responses were measured after 5 days in culture by [3H]-thymidine incorporation, their interferon production was measured after 24 hr and 5 days, and natural killer (NK) cell activation was measured after 24 hr and 5 days of culture. Blastogenic responses to viruses were significantly low for only HSV, type 1:1.75 X 10(3) cpm in patients' cells compared to 6.36 for controls. Interferon responses to all three viruses were significantly low at both 24 hr and 5 days; e.g., HSV, type 1:139 IU/ml in patients' cells compared to 777 for controls at 24 hr. NK cell responses of patients were lower than those of controls when tested fresh and after 24 hr of incubation: 6.1 versus 11.7% and 9.2 versus 16.8% target cell lysis, respectively. Exposure to viruses boosted NK cell responses of both patients' and controls' cells, but boosting was generally greater among the normal rather than the patients' cells. The abnormalities of response were present in all three patient groups. Addition of interleukin-2 in vitro increased the patient and control blastogenic and NK responses but did not augment the interferon responses. The in vitro responses to both HSV, type 1, and HSV, type 2, correlated significantly with our conventional assays of the percentage and absolute level of T4+-helper lymphocytes in the blood and the blastogenic responses to mitogens, such as phytohemagglutinin, pokeweed mitogen, and concanavalin A. This system should be useful for the study of host defense in acquired immune deficiency syndrome patients and those in high-risk groups, and also for the in vitro evaluation of immunomodulators.

Acquired Immunodeficiency Syndrome↗
PubMed1985

High rate of long-term survival in adult acute leukemia following ten-day chemotherapy (OAP) induction. Maintenance with chemotherapy or chemotherapy plus BCG vaccine.

In this Southwest Oncology Group (SWOG) study, 216 adults with acute leukemia were treated with ten-day chemotherapy consisting of vincristine sulfate (Oncovin), cytarabine (ara-C) (100 mg per square meter of body area per day by 24-hour infusion), and prednisone (ten-day OAP). The results were compared with those of a previous SWOG study in which cytarabine (200 mg per square meter of body area per day) was given for five days (five-day OAP). Patients entering complete remission (CR) were given three consolidation courses of five-day OAP and randomized to maintenance chemotherapy alone (32 patients) or combined with BCG vaccine (24 patients). For 160 previously untreated patients with acute myelogenous leukemia, there was no difference in remission rates (53% vs 43%) or median survival times (48 vs 47 weeks) between ten-day and five-day OAP. The difference in duration of CR (74 vs 54 weeks, respectively) between the two maintenance arms was not statistically significant. However, 14% of evaluable patients with acute myelogenous leukemia and 26% of those achieving CR were alive and in remission more than five years.

Acute Disease↗
PubMed1985

Pharmacokinetics, single-dose tolerance, and biological activity of recombinant gamma-interferon in cancer patients.

We report a clinical study of the pharmacokinetics, toxicity, and biological activity of i.v.- and i.m.-administered recombinant gamma-interferon (rIFN-gamma) consisting of 143 amino acids. Ten patients with metastatic cancer were given rIFN-gamma at doses of 0.01 to 2.5 mg/sq m by alternating i.m. and i.v. bolus injections with a minimum intervening period of 72 h. After i.v. administration, rIFN-gamma was cleared monoexponentially with a short half-life of 25 to 35 min as determined by bioassay and enzyme immunoassay. After i.m. injection, a longer half-life of 227 to 462 min was measured by enzyme immunoassay. Serum titers were detected by bioassay only at high doses, suggesting partial loss of antiviral activity at the i.m. site. However, other biological effects were retained as evidenced by fever, chills, and fatigue after both routes of administration and granulocytopenia after i.m., but not i.v., doses. Two of ten patients showed objective evidence of tumor regression. These data suggest that further studies with i.m. as well as prolonged i.v. infusions of rIFN-gamma are indicated.

Half-Life↗
PubMed1985

Modification of human leukocyte interferon pharmacology with a monoclonal antibody.

The antitumor and antiviral properties of the interferons have been well established. However, the usefulness of the interferons may be limited, in part, because of rapid clearance from the plasma and degradation by plasma or tissue enzymes. A monoclonal antibody (IFG-252.2) was developed which binds to recombinant DNA-produced human alpha-interferon (rIFN-alpha A) without measurably reducing its in vitro antiviral or antiproliferative properties. Pharmacokinetic studies of rIFN-alpha A:antibody complex in the intact, anesthetized rat showed that rIFN-alpha A activity cleared from plasma 3-fold slower than found after injection of free rIFN-alpha A. This resulted in a 15-fold increase in its calculated area under concentration curve compared to that of free rIFN-alpha A. These studies suggest that interferon bound to a monoclonal antibody may provide a means to prevent the normal clearance and degradation of free interferon and may result in prolonged antitumor and antiviral plasma activity in vivo. Furthermore, it suggests that monoclonal antibodies to various biologically active agents may be used to favorably alter their pharmacokinetics while leaving their biological activity unaltered.

Animals↗
PubMed1984

Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer.

The conditions of ten patients with metastatic renal cell carcinoma were serially evaluated by neuropsychiatric examination to determine the nature of the fatigue-asthenia symptoms resulting from human leukocyte interferon alpha therapy. The majority of the patients had moderate to severe behavioral changes and mild to moderate cognitive, affective, and personality changes within the first week of daily intramuscular administration of 3 X 10(6) units of interferon. This descriptive clinical study suggests that the intense fatigue may be a manifestation of a complex neurotoxicity, most suggestive of frontal lobe changes, and resulting in neurasthenia syndrome with reversible impairment of some higher mental functions.

Adenocarcinoma↗
PubMed1984

Alpha interferon for induction of remission in hairy-cell leukemia.

We treated seven patients who had progressive hairy-cell leukemia with daily doses of 3 million units of partially pure alpha (leukocyte) interferon by the intramuscular route. Three patients had a complete remission, and four had a partial remission, according to strict criteria for a response. After treatment, bone-marrow aspirates showed an absence of leukemia cells in three patients and 5 per cent or fewer in three others. Normalization of subnormal peripheral-blood values occurred in six of six patients with anemia, in seven of seven with granulocytopenia, and in four of four with thrombocytopenia. Remissions have been maintained for over 6 to over 10 months. Alpha interferon appears to be highly effective in patients with hairy-cell leukemia.

Adult↗
PubMed1984

Collaborative phase I-II study of recombinant DNA-produced leukocyte interferon (clone A) in metastatic breast cancer, malignant lymphoma, and multiple myeloma.

Fifty-two patients with advanced cancer received sequentially escalating doses of 3 to 50 million units of recombinant DNA-produced alpha interferon by daily intramuscular injection. There were 23 patients with metastatic breast cancer, 17 patients with nodular poorly differentiated lymphocytic lymphoma, and 12 patients with multiple myeloma. Complete and partial remissions were obtained in 35 percent of patients with nodular poorly differentiated lymphoma, whereas rare activity was found in breast cancer and multiple myeloma. Dose-limiting toxicity occurred in patients receiving 36 million units or more and consisted of fatigue/asthenia, weight loss, and elevation of transaminase levels, requiring frequent interruption, reduction in dose, or cessation of treatment. Hematologic toxicity was rarely a limiting factor, but myelosuppression was severe in some patients with multiple myeloma. All toxicities were reversible on discontinuation of treatment. Antibodies to recombinant leukocyte A interferon were seen infrequently but may adversely affect therapy.

Adult↗
PubMed1984

Induction of proteins in human lymphoblastoid cells by recombinant alpha interferon.

Two-dimensional gel electrophoresis, using either silver staining or pulse labeling with 35S-L-methionine and autoradiography, was employed to determine changes in the synthesis of proteins that may be involved in the antiproliferative effects of recombinant alpha interferon (IFNrA) on Burkitt's lymphoma Daudi cells. IFNrA initiated and/or augmented the synthesis of at least 13 proteins that were distinct in molecular weights and isoelectric properties. Synthesis of several of these IFN-enhanced proteins was inhibited by actinomycin-D, an inhibitor of mRNA synthesis. Although IFN-induced antiproliferative effects were observed at 48 h, an increase in the synthesis of several proteins was observed as early as 3 h. The levels of these IFN-enhanced proteins in treated cells continued to increase through 24 h. At least two proteins of approximately 17 kD were observed to be synthesized in IFN-treated cells but not in control cells. Neither inhibition of synthesis of any particular protein nor post-synthetic modification of proteins in response to IFNrA was observed with these methods. The results of this study are compared and contrasted to those of several other laboratories.

Burkitt Lymphoma↗
PubMed1984

Immunologic studies of the acquired immune deficiency syndrome: relationship of immunodeficiency to extent of disease.

Immunologic and conventional laboratory studies were done in 135 previously untreated subjects including 28 (20.7%) symptom-free homosexuals and 74 (54.8%) with ARC and 33 (24.5%) with AIDS. More than half of all patients had abnormal percentages of lymphocytes, percentages of T3+ cells, percentage and absolute number of T4+ cells, percentage of T8+ cells, T4/T8 ratio, monocyte adherence, and serum thymosin alpha 1. Most immune variables worsened with progressive disease. Low lymphocyte 5'nucleotidase increased suppressor cell activity, and impaired IL-2 and alpha interferon production and response suggest diminished mature and increased immature peripheral blood and tissue T cells. These findings suggest approaches to staging, prognostication, and treatment for AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Synergistic antiproliferative activity of leukocyte interferon in combination with alpha-difluoromethylornithine against human cells in culture.

alpha-Difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was administered in combination with human leukocyte interferon to human lymphoblastoid (Daudi) cells in culture. True synergistic antiproliferative activity was observed at 72 hr after continuous exposure. This effect was observed regardless of the ratio of interferon to alpha-difluoromethylornithine concentrations. Although the mechanisms by which this effect occurs are unknown, these studies provide a rationale for combination clinical trials of alpha-difluoromethylornithine with leukocyte interferon.

Antineoplastic Agents↗
PubMed1984

Pharmacokinetic study of partially pure gamma-interferon in cancer patients.

A pharmacokinetic study was performed with partially pure immune (gamma) interferon (IFN-gamma) in patients with metastatic cancer. Nine patients were given IFN-gamma by the i.m. route in doses ranging from 1.5 X 10(5) to 9.6 X 10(6) antiviral units. There was no detectable antiviral activity in patients' serum, and only minimal side effects were observed. Fifteen patients were given IFN-gamma by i.v. bolus infusion in doses ranging from 1.5 X 10(5) to 54 X 10(6) units. Serum clearance of antiviral activity was described by a monoexponential disappearance curve. The serum half-life was dose dependent (3 min at the lower doses and 34 min at the highest doses). There were few consistent biological effects observed in the patients. Based on these pharmacokinetic data, eight patients were treated by a 6-hr continuous infusion consisting of 3 X 10(6) units by i.v. bolus followed by 4 X 10(6) units/hr for 6 hr. This regimen resulted in consistent serum levels of IFN-gamma ranging from 40 to 60 units over the 6-hr period. Marked granulocytopenia occurred within 24 hr and was sustained during the 10-day infusion period. There was marked increase in serum beta 2-microglobulin. We conclude that, in order to induce consistent serum antiviral activity, partially pure IFN-gamma, because of its rapid serum disappearance curve, must be administered by continuous i.v. infusion.

Drug Evaluation↗
PubMed1983

Antibodies to human leucocyte interferons in cancer patients.

During the course of clinical investigation of partly purified human leucocyte interferon (IFN) prepared at the Finnish Red Cross (PIF), neutralising IgG antibodies to human leucocyte IFN were detected in the sera of 3 patients with cancer. In 2 of these patients, the antibodies were detected in serum before treatment with PIF. In the third patient antibodies developed during the course of treatment. Antibody titres against six recombinant human leucocyte IFN sub-types and one recombinant hybrid human leucocyte IFN were different in the 3 patients.

Antibodies↗
PubMed1983

Human leukocyte interferon to control thrombocytosis in chronic myelogenous leukemia.

Nine patients with refractory chronic myelogenous leukemia and severe symptomatic thrombocytosis (greater than or equal to 1 X 10(6) platelets/mm3) were given partially purified human leukocyte interferon-alpha. A significant decline in platelet counts, from a mean (+/- SE) of 1.71 +/- 0.53 X 10(6)/mm3 to a mean of 0.52 +/- 0.24 X 10(6)/mm3 (p less than 0.01), resulted in all patients. Maintenance of low platelet counts was achieved in two patients for more than 143 and 300 days, respectively. Treatment with human leukocyte interferon-alpha was stopped in the remaining patients because of increases in the leukocyte count, toxicity, or both. Our preliminary observations suggest that human leukocyte interferon-alpha may significantly alleviate progressive thrombocytosis in advanced chronic myelogenous leukemia. Further studies of human leukocyte interferon-alpha and chemotherapeutic agents are indicated.

Adult↗
PubMed1983

Clinical study of recombinant DNA-produced leukocyte interferon (clone A) in a intermittent schedule in cancer patients.

The effects of recombinant DNA-produced leukocyte interferon (IFLrA) were studied in 37 patients with metastatic cancer who received sequentially escalating doses of 9-86 million units (MU) of IFLrA by im injection twice weekly. The IFLrA was absorbed rapidly and reached a peak serum concentration 6-8 hours after injection. Serum concentration of IFLrA increased proportionately with the dose. The most common side effects included fever, chills, asthenia, anorexia, and weight loss, and leukopenia, granulocytopenia, and lymphopenia occurred frequently. Elevation of serum glutamic-oxaloacetic transaminase was frequent above doses of 50 MU. All side effects were reversible by discontinuation of the drug. Antibodies to IFLrA were detected in 3 patients while on treatment. The presence of antibodies coincided with drastic reduction in serum IFLrA concentration and, in 1 patient, with relapse of disease. Objective tumor responses were documented in patients with lymphomas but not in other groups of patients.

Adolescent↗
PubMed1983

Leukocyte interferon-induced myeloid cytoreduction in chronic myelogenous leukemia.

We investigated the antiproliferative effect of partially purified human leukocyte interferon (HuIFN-alpha) given in a dose of 9-15 X 10(6) U daily by intramuscular injection to 7 patients with chronic myelogenous leukemia (CML). Hematologic remission of the disease was obtained in 5 patients. Among the responding patients, the mean white blood cell count decreased from 97.4 X 10(3)/cu mm (range from 35 X 10(3)/cu mm to 239 X 10(3)/cu mm) to 4.2 X 10(2)/cu mm (range from 3.0 X 10(3) to 7.9 X 10(3) cu/mm). Parallel reduction occurred in serum B12, from a mean of 1,435 pg/ml to a mean of 726 pg/ml, and lactate dehydrogenase levels, from a mean of 325 mU/ml to 112 mU/ml. Enlarged spleens decreased in 3 of 3 patients. The 5 responding patients have been maintained on HuIFN-alpha, 3 X 10(6) U daily or every other day, for 6+-35+ wk.

Chromosome Aberrations↗