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We report ultrahigh-sensitivity static strain sensing (noise equivalent strain
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Classical psychoanalytic technique, which called for the role of the analyst to be a scientific observer, removed from interaction with the patient, imposed such restrictions on the analyst that often his or her simple human responsiveness to the patient was curtailed. Harry Stack Sullivan revolutionized the field by introducing the concept of "participant observation," and others of his time made similar observations. Gradually, over the years, analysts have become more real, more human, and more interactive with their patients. Contrary to classical opinion, this departure from the original technique does not interfere with analytic work, and, in fact, enhances it, if the analyst monitors and analyzes the reactions of patients to this more human engagement. Examples are provided to support this conclusion.
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A total of 22 patients with advanced measurable colorectal carcinoma were treated with human lymphoblastoid interferon, 15 X 10(6) U/m2 im 3 times a week, in a trial designed to evaluate therapeutic activity, toxic effects, and biological response modification. One partial response (4.5% response rate) was observed which lasted 4 months. Sixty-eight percent of the patients required dose reduction for excessive toxicity, primarily constitutional symptoms. One patient developed phenobarbital toxicity, a previously undescribed side effect thought to be related to interferon-induced depression of hepatic microsomal enzymes required for drug metabolism. Treatment was associated with an increase in peripheral blood natural killer (NK) cell activity and the activity of an interferon-induced enzyme, 2'-5' oligoadenylate synthetase. The increase in NK cell activity was observed only in patients whose pretreatment NK cell activity was below normal. No induction of serum factors inducing differentiation of myeloid leukemic cell lines was documented. We conclude that human lymphoblastoid interferon, at the dose and schedule tested, has minimal antitumor activity as a single agent in advanced colorectal cancer and induces unacceptable toxicity in the majority of such patients. Recent literature suggesting a possible role for interferon alpha in combination with other drugs in the treatment of colorectal cancer is discussed.
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Neoplasias del Colon/terapia , Interferón Tipo I/uso terapéutico , Neoplasias del Recto/terapia , Adulto , Anciano , Neoplasias del Colon/patología , Femenino , Humanos , Interferón Tipo I/efectos adversos , Interferón Tipo I/sangre , Células Asesinas Naturales , Linfocitos/enzimología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias del Recto/patologíaRESUMEN
Interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) was used to treat sequential groups of patients with Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS). Major antitumor effects (complete or partial responses) were observed in 38% of the patients treated initially with high-dose interferon alfa-2a and in 17% of patients in whom the dose was increased after low-dose treatment failed. A low dose of interferon alfa-2a was ineffective; one patient (3%) showed a partial response. Patients whose tumors responded to interferon treatment showed a significantly lower rate of opportunistic infection, as well as a longer survival than nonresponders. The status of pretreatment immune function was important in predicting the response to interferon treatment. The implication of these findings with respect to understanding the mechanism of action of interferon and the definition of the most appropriate patients for interferon treatment are discussed.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , Interferón Tipo I/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Sarcoma de Kaposi/terapia , Adulto , Antígenos de Diferenciación de Linfocitos T , Antígenos de Superficie/análisis , Humanos , Inmunidad , Masculino , Pronóstico , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/fisiopatología , Linfocitos T/inmunologíaRESUMEN
The mode of action of rat interferon (IFN) on growth of the R3230AC mammary adenocarcinoma was studied in vivo in Fischer female rats. A dose of 1 X 10(4) units of rat IFN given thrice weekly inhibited the growth of the transplanted mammary tumors. Of the five eicosanoids measured in the tumor, the content of four arachidonate products, prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2, was higher in mammary tumors from IFN-treated rats than the control rats. PGE2 was the major eicosanoid. In vitro PG synthesis (PGE1, PGE2, and PGF2 alpha) was lower in tumor microsomes prepared from IFN-treated tumors. These data suggest that the tumor content of four arachidonate products in the IFN-treated tumors was related to the in vivo effects of rat IFN. Indomethacin, a cyclooxygenase inhibitor, also inhibited tumor growth. Furthermore, when indomethacin was administered daily in combination with rat IFN, the tumor-inhibiting effect of rat IFN was reduced. These observations suggest that the effects of eicosanoids appear to be biphasic in this tumor model. Inhibition of arachidonic acid metabolism resulted in tumor growth inhibition, a finding consistent with the view that eicosanoid production is required for tumor enhancement. Conversely, in the experiments with rat IFN, retardation of tumor growth is associated with a greater amount of arachidonic acid metabolism, and indomethacin prevents this effect. Eicosanoids appear to be required for tumor-inhibiting effects of rat IFN, and yet inhibition in vivo of eicosanoid synthesis also resulted in retardation of tumor growth. Although the precise mechanism of action in each situation is unclear, these apparently contradicting results are consistent with the biphasic actions of eicosanoids reported in some normal tissues and transformed tumor cell lines.
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Adenocarcinoma/metabolismo , Interferones/farmacología , Neoplasias Mamarias Experimentales/metabolismo , Prostaglandinas/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/terapia , Animales , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Femenino , Indometacina/farmacología , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/terapia , Prostaglandina-Endoperóxido Sintasas/análisis , Prostaglandinas/análisis , Ratas , Ratas Endogámicas F344RESUMEN
Multivariate analysis was used to identify which of a large number of pretreatment immunological parameters correlated with therapeutic response, subsequent development of opportunistic infection, and survival from the time of diagnosis in a group of 70 patients with Kaposi's sarcoma and acquired immunodeficiency syndrome treated with recombinant leukocyte A interferon. In a logistic regression model, delayed type hypersensitivity response to one or more recall antigens and high proliferative response to Escherichia coli were significant predictors for response to recombinant leukocyte A interferon (for the model, P = 0.01). For prediction of the development of opportunistic infection, the model selected low proliferative responses to phytohemagglutinin and E. coli (P less than 0.001). Favorable factors predicting survival in the Cox regression model were the absence of endogenous serum interferon activity and a high proliferative response to E. coli (P less than 0.001). The estimated median survival for the group with endogenous serum interferon activity and low E. coli response was 12 months; the median has not yet been reached for the group with no serum interferon and a high E. coli response. We conclude that immunological parameters may be useful in predicting prognosis in patients with Kaposi's sarcoma and acquired immunodeficiency syndrome.
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Síndrome de Inmunodeficiencia Adquirida/inmunología , Sarcoma de Kaposi/inmunología , Síndrome de Inmunodeficiencia Adquirida/terapia , Antígenos de Diferenciación de Linfocitos T , Antígenos de Superficie/análisis , Humanos , Hipersensibilidad Tardía/inmunología , Inmunoglobulinas/análisis , Interferón Tipo I/uso terapéutico , Interferones/sangre , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Pronóstico , Proteínas Recombinantes/uso terapéutico , Sarcoma de Kaposi/terapia , Pruebas Cutáneas , Linfocitos T/clasificación , Factores de Tiempo , Microglobulina beta-2/análisisRESUMEN
Considerably augmented chemiluminescence (CL) occurred when murine peritoneal resident macrophages (MPs), pretreated with murine interferon (MuIFN)-alpha within 24 hr, were stimulated by 4-beta-phorbol, 12-beta-myristate, 13-beta-acetate (PMA). Augmentation of CL generation ceased when incubation in the presence of MuIFN was continued for 48 hr. As 12 hr preincubation with MuIFN procured optimal CL generation, the various reactive oxygen species (OH, O2-., H2O2) were measured at that point. The hydroxyl radical (OH.) level in MuIFN-treated MPs was 19.44 times higher than in MuIFN-untreated MPs. However, the levels of O2-. and H2O2 generation were the same in both MuIFN-treated and untreated MPs. Moreover, by using the inhibitors lipoxygenase and cyclo-oxygenase, we established clearly that CL and OH. generation in MuIFN-treated MPs is due to the lipoxygenase pathway of arachidonic acid metabolism.
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Interferón Tipo I/farmacología , Mediciones Luminiscentes , Macrófagos/metabolismo , Forboles/farmacología , Acetato de Tetradecanoilforbol/farmacología , Animales , Azidas/farmacología , Catalasa/farmacología , Catecoles/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Peróxido de Hidrógeno/metabolismo , Masoprocol , Ratones , Ratones Endogámicos C57BL , Consumo de Oxígeno , Azida Sódica , Superóxido Dismutasa/farmacología , Factores de Tiempo , ZimosanRESUMEN
Two cytokines, interferon (IFN) and interleukin 2 (IL-2), activate murine natural killer (NK) cells in vitro. Together both factors synergize considerably. Antibody against IFN eliminates the response of NK cells to IFN as well as to IL-2, whereas antibody against IL-2 blocks the effect of IL-2 but not of IFN. These findings as well as previous observations imply that both factors act on the same cell but have different roles. We suggest that IFN induces NK cell activation and IL-2 enhances this effect. Further studies revealed that besides inducing cytotoxicity in NK cells IFN induces the production of prostaglandin E (PGE) which inhibits NK cell activation. We propose therefore that IFN has a dual effect on NK cells: it induces NK cells to become cytotoxic and initiates a negative feedback by increasing the production of PGE. IL-2, which synergizes with IFN in the activation of NK cells, ceases to do so when the negative feedback (PGE-mediated) is blocked with indomethacin. We infer that IL-2 enhances NK cell activity by interfering with the negative feedback rather than by aiding NK cell activation.
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Citotoxicidad Inmunológica , Inmunidad Innata , Interleucina-2/inmunología , Células Asesinas Naturales/inmunología , Animales , Reacciones Antígeno-Anticuerpo , Células Cultivadas , AMP Cíclico/fisiología , Citotoxicidad Inmunológica/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Indometacina/farmacología , Interferones/inmunología , Interferones/fisiología , Ratones , Prostaglandinas E/farmacologíaRESUMEN
KIE: An overview is provided of what is currently known about the epidemiology of acquired immunodeficiency syndrome (AIDS) and its potential for spread. It is concluded that AIDS poses a worldwide threat to public health of proportions unprecedented in modern times. The federal government is faulted for its limited support of clinical research on antiviral substances to suppress the multiplication of the AIDS-associated virus.^ieng
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Síndrome de Inmunodeficiencia Adquirida , Síndrome de Inmunodeficiencia Adquirida/sangre , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/etiología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/mortalidad , Síndrome de Inmunodeficiencia Adquirida/terapia , Síndrome de Inmunodeficiencia Adquirida/transmisión , África , Investigación Biomédica , Deltaretrovirus , Brotes de Enfermedades , Ensayo de Inmunoadsorción Enzimática , Europa (Continente) , Gobierno Federal , Femenino , Haití , Homosexualidad , Humanos , Masculino , Política Pública , Asignación de Recursos , Infecciones por Retroviridae/terapia , Riesgo , Factores Sexuales , Trastornos Relacionados con Sustancias/complicaciones , Linfocitos T , Factores de Tiempo , Estados UnidosAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Interferón Tipo I/uso terapéutico , Sarcoma de Kaposi/terapia , Anticuerpos Monoclonales/análisis , Humanos , Interferón Tipo I/administración & dosificación , Masculino , Pronóstico , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/inmunologíaRESUMEN
Naturally produced beta-interferon was evaluated following i.m. and i.v. administration to 18 patients with advanced cancer. Fever (mean +/- S.E. = 38.1 degrees +/- 1.7 degrees), enhancement of natural killer cell cytotoxicity, and depression of the white blood cell count occurred following a single i.m. injection in the absence of detectable serum antiviral activity. Fever, rigors, and fatigue were dose-limiting toxicities following daily i.v. administration of 10 million units. Tachyphylaxis, as reported following repetitive administration of alpha-interferons, did not occur. Side effects, depression of the white blood cell count, and enhancement of natural killer cell cytotoxicity were similar when beta-interferon was administered daily as a 10-min bolus or as a 6-hr infusion. However, while natural killer cell cytotoxicity increased progressively over 10 days of bolus injections, it was maximal after the initial 6-hr infusion of beta-interferon. Administration of 10 million units of beta-interferon divided equally between a 10-min bolus injection and a 3-hr infusion was well tolerated and resulted in high initial peak and lower sustained serum interferon levels. Based on pharmacokinetic criteria, this schedule of administration can be recommended for further study in Phase II trials. However, in light of the biological activity of beta-interferon following i.m. administration, the level of beta-interferon in the serum may have limited value as a predictor of antitumor response, toxicity, or biological response modification.
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Interferón Tipo I/administración & dosificación , Neoplasias/terapia , American Cancer Society , Neoplasias de la Mama/terapia , Carcinoma de Células Renales/terapia , Neoplasias del Colon/terapia , Evaluación de Medicamentos , Humanos , Interferón Tipo I/biosíntesis , Interferón Tipo I/metabolismo , Neoplasias Renales/terapia , Cinética , Linfoma/terapia , Masculino , Poli I-C/farmacología , Piel/metabolismo , Estados UnidosRESUMEN
Human leukocyte-derived alpha interferon [HuIFN-alpha(Le)] has been purified and/or concentrated on Carboxymethyl derivatized Controlled Pore Glass (CML-CPG240) beads. These glass beads adsorb HuIFN-alpha(Le) efficiently at acid pH and at physiological ionic strengths. Elution of HuIFN-alpha(Le) may be accomplished by several methods. Using buffers at relatively high ionic strengths (approximately 0.6 M) and pH values ranging from 2.6 to 6.9 for elution, preparations with specific activities of 10(5)-10(6) IU/mg were obtained with approximately 90 percent recoveries. Alternatively, using elution buffers at the same high ionic strength and at pH values ranging from 7.0 to 8.0, five-fold or better concentration and complete recovery of crude HuIFN-alpha(Le) were achieved. The resulting preparations were suitable for direct application to an antibody affinity chromatography column.
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Cromatografía/métodos , Interferón Tipo I/aislamiento & purificación , Leucocitos/análisis , Adsorción , Vidrio , HumanosAsunto(s)
Interferón Tipo I/uso terapéutico , Sarcoma de Kaposi/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intramusculares , Células Asesinas Naturales/efectos de los fármacos , Sarcoma de Kaposi/complicaciones , Sarcoma de Kaposi/inmunología , Factores de TiempoAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Homosexualidad , Linfadenopatía Inmunoblástica/inmunología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Adulto , Humanos , Linfadenopatía Inmunoblástica/complicaciones , Linfadenopatía Inmunoblástica/fisiopatología , Interferones/sangre , Ganglios Linfáticos/patología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Estudios Prospectivos , Sarcoma de Kaposi/complicacionesRESUMEN
Dilution of human fibroblast GM2767 cell cultures into fresh serum-containing growth medium induces ornithine decarboxylase activity 45-fold over a six-hour interval. When the fibroblast cultures are supplemented with human fibroblast alpha-, beta-, or gamma-interferon at the time of dilution into fresh growth medium, the induction of ornithine decarboxylase is inhibited 61%, 90%, and 65%, respectively. beta-Interferon is the most effective type of interferon to inhibit induction of ornithine decarboxylase.
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Carboxiliasas/antagonistas & inhibidores , Interferón Tipo I/farmacología , Interferón gamma/farmacología , Inhibidores de la Ornitina Descarboxilasa , Células Cultivadas , Inducción Enzimática/efectos de los fármacos , HumanosRESUMEN
We report here on the development of (a) a double-antibody radioimmunoassay and (b) a solid-phase radioimmunoassay for cloned human interferon-alpha (leukocyte) [HuIFN-alpha(Le)]. We present the results of titrations of human interferon-alpha-2 (HuIFN-alpha 2) using either method under experimental and optimized conditions. A comparative study of the two methods indicates that (a) the double-antibody procedure is 200-fold more economical of antibody when quantitations are carried out within an optimal range of 0.05--1.0 ng; (b) the double-antibody method is fivefold more sensitive than the solid-phase method, its sensitivity being within the range of the antiviral assays for interferons; and (c) the solid-phase assay is significantly faster. The data also support the presence in human serum of a factor(s) that decreases the maximal amount of HuIFN-alpha 2 bound to antibody. We conclude that these radioimmunoassays are superior to biological assays for the quantitation of interferon-alpha polypeptides from the standpoints of objectivity and reproducibility as well as time and effort required.
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Interferón Tipo I/análisis , Clonación Molecular , Humanos , Interferón Tipo I/inmunología , Radioinmunoensayo/métodosRESUMEN
The potential feasibility of using exogenously administered human interferon for the treatment of selected cases of leishmaniasis prompted us to study the effects of murine interferon on the course of Leishmania tropica infection in C57Bl/6 mice. L cell-derived mouse interferon was administered daily by intraperitoneal (1,000 and 10,000 U) or intralesional (100 U) injection in mice inoculated into footpads with L. tropica amastigotes. Footpad swelling and tissue parasite density were assessed over the course of infection. Interferon treatment did not significantly affect these clinical and parasitological parameters. Furthermore, addition of interferon (100--100,000 U) to cultures of amastigote-infected mouse peritoneal macrophages or to axenic cultures of promastigotes did not affect replication. We conclude that interferon lacks intrinsic antileishmanial activity and does not significantly enhance host defense against Leishmania.