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Biomedical subjects

R J Spiegel

Publications and source records attributed to R J Spiegel.

At least 19 recordsLinked to original sources
PubMed1989

Cost-benefit analysis of interferon alfa-2b in treatment of hairy cell leukemia.

The clinical benefits as well as the cost benefits of use of recombinant interferon (IFN) alfa-2b instead of conventional chemotherapy (primarily chlorambucil) for progressive hairy cell leukemia were assessed retrospectively on the basis of 12 months of clinical data from 128 patients treated with IFN alfa-2b. Data from 71 matched historical control patients who had received conventional treatment were used for survival analysis. Hematologic response (reversal of cytopenias) was achieved by 18% of the control patients versus 73% of the IFN-treated patients. This response was associated with virtual elimination of the need for transfusions and splenectomy as well as dramatic decreases in the frequency of fatal infections (22.5% vs. 1.6%) and the 12-month mortality rate (28% vs. 3.1%). Direct costs per patient per year for medical care (transfusions, antibiotic treatment, splenectomy, and chemotherapy) of those receiving IFN alfa-2b were 2.8-fold lower than costs for medical care of control patients ($5,027 vs. $14,046). Indirect costs, which reflect the present value of future earnings lost due to premature death, were 13.3-fold lower for IFN-treated patients than for control patients ($4,771 vs. $63,507). Our analysis demonstrates that IFN alfa-2b offers substantial clinical and cost advantages to patients with hairy cell leukemia and that the introduction of this therapy using novel biotechnology furthers the health care community's commitment to cost containment.

Adult↗
PubMed1989

Alpha interferons: a clinical overview.

The development of the recombinant alpha interferons has provided a prototype for the clinical development of biological compounds. Over 5,000 patients have now been treated with alpha interferons, and from this experience, some general principles relating to the phase I-III testing of biologicals have emerged. Clinical trials of alpha interferon have suggested dose-response relationships and provided a clearer picture of schedule dependence. These trials have also indicated that the extent of tumor burden and identification of sensitive patient subtypes may be critical factors affecting the potential activity of biological compounds. Recent studies using interferon in the treatment of chronic viral hepatitis have also generated promising results, suggesting an even greater antiviral role for the drug. The toxicity profile of the alpha interferons is unusual. Fever and influenza-like symptoms occur in almost all patients at all doses and schedules, and are usually dose limiting. Somnolence and other generally mild CNS effects occur in a small percentage of patients. Hematologic toxicity occurs but is minimal at lower doses and is noncumulative and rapidly reversible at all doses. Gastrointestinal toxicity is mild. No other unusual or unexpected toxicities have been reported, and early reports of cardiovascular toxicity have not been confirmed in large trials. The full role of alpha interferon in antineoplastic and antiviral therapy will be resolved in the coming years. This review summarizes existing safety and efficacy data for the alpha interferons.

Combined Modality Therapy↗
PubMed1989

Comparison of finite-difference time-domain SAR calculations with measurements in a heterogeneous model of man.

A finite-difference time-domain technique was used to calculate the specific absorption rate (SAR) at various sites in a heterogeneous block model of man. The block model represented a close approximation to a full-scale heterogeneous phantom model. Both models were comprised of a skeleton, brain, lungs, and muscle. Measurements were conducted in the phantom model using an implantable electric-field probe and a computer-controlled data acquisition system. The calculation and measurement of SAR distributions were compared primarily in the head (including the neck) and chest. To obtain the necessary spatial resolution with the computer model, the head and neck were modeled with approximately 105,000 cells, while 86,000 cells were used to configure the chest. Planewave fields, polarized in the E orientation, were utilized to irradiate the models at an exposure frequency of 350 MHz. Reasonable correlation existed between the calculations and measurements.

Absorption↗
PubMed1989

Anti-interferon antibodies to interferon-alpha 2b: results of comparative assays and clinical perspective.

Previous studies have reported a low (less than 3%) incidence of anti-interferon (IFN) serum neutralizing antibodies following treatment with IFN-alpha 2b. Since this result contrasts with a higher incidence reported with IFN-alpha 2a, the question has been raised whether differences in assay techniques and patient comparability rather than inherent differences in the molecules might account for the reported differences in antibody incidence. In this report two patient groups, 151 hairy cell leukemia (HCL) patients and 101 patients with other malignancies, who have received long-term dosing with IFN-alpha 2b, are reported. The sera of both groups were studied before, during and after treatment by various assay methodologies. Utilizing three assay techniques, a less than 3% overall incidence of serum antibody formation was confirmed in these retested samples. With over 575 samples tested in multiple assays, the radioimmunoassay, as utilized in prior reports, demonstrated 99% agreement with a bioassay. Therefore, prior speculation that the assay technique for IFN-alpha 2b might produce a high false-negative rate was disproven. Additionally, the clinical outcome of these patients also failed to demonstrate a pattern of clinical relapse. In summary, these new analyses confirm the low (less than 3%) incidence of neutralizing antibody development following treatment with IFN-alpha 2b and confirm that no high rates of clinical relapse have developed in patients treated with chronic long-term dosing. Assay methodology does not appear to be a likely explanation for the low incidence of antibody formation reported with IFN-alpha 2. Rather, the unique molecular structure and pharmaceutical formulation of IFN-alpha 2b remains the most likely explanation of its minimal antigenicity.

Antibodies↗
PubMed1988

Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon.

The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study.

Adult↗
PubMed1988

Effect of ambient levels of power-line-frequency electric fields on a developing vertebrate.

Fertilized eggs of Gallus domesticus were exposed continuously during their 21-day incubation period to either 50- or 60-Hz sinusoidal electric fields at an average intensity of 10 Vrms/m. The exposure apparatus was housed in an environmental room maintained at 37 degrees C and 55-60% relative humidity (RH). Within 1.5 days after hatching, the chickens were removed from the apparatus and tested. The test consisted of examining the effect of 50- or 60-Hz electromagnetic fields at 15.9 Vrms/m and 73 nTrms (in a local geomagnetic field of 38 microT, 85 degrees N) on efflux of calcium ions from the chicken brain. For eggs exposed to 60-Hz electric fields during incubation, the chicken brains demonstrated a significant response to 50-Hz fields but not to 60-Hz fields, in agreement with the results from commercially incubated eggs [Blackman et al., 1985a]. In contrast, the brains from chicks exposed during incubation to 50-Hz fields were not affected by either 50- or 60-Hz fields. These results demonstrate that exposure of a developing organism to ambient power-line-frequency electric fields at levels typically found inside buildings can alter the response of brain tissue to field-induced calcium-ion efflux. The physiological significance of this finding has yet to be established.

Animals↗
PubMed1988

Treatment of epidemic Kaposi's sarcoma with a combination of interferon-alpha 2b and etoposide.

A prospective clinical trial of concomitant interferon-alpha 2b and etoposide was conducted in 24 previously untreated patients with epidemic Kaposi's sarcoma. Eight of 21 evaluable patients (38%) achieved either a complete response (1 patient) or a partial response (7 patients). None of the responders had a prior history of opportunistic infection. Hematologic toxicity was severe, and 8 patients developed an opportunistic infection. The combination of interferon-alpha 2b and etoposide has modest activity, but no additive or synergistic activity was evident in the dose and schedule utilized in this study. The exact role for interferon-alpha in epidemic Kaposi's sarcoma, both as a single agent and in combinations, remains to be determined.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Minimal antigenicity of intron A in human recipients demonstrated by three analytical methods.

Antibodies to recombinant human interferon alpha 2b (Intron A) were detected in only a small number of 101 Intron A recipients. This group of cancer patients received Intron A for a mean treatment time of 4.3 months and were selected from disease categories in which subjects were expected to be immunocompetent. Three methods for the detection of antibodies were employed: (a) a bioassay measuring the neutralizing activity of the sera for the antiviral action of interferon alpha 2b, (b) a radioimmunological assay measuring the ability of the sera to prevent the detection of interferon alpha 2b by an immunoradiometric assay (IRMA), and (c) an enzyme-linked immunosorbent assay (ELISA) that measures the binding of immunoglobulins to interferon alpha 2b attached to a solid support. Three of the 101 patients developed neutralizing activity during treatment. Two of these exhibited low neutralizing titers of 1:6-1:9 and were unreactive in the IRMA and ELISA, while only one was positive by bioassay, IRMA, and ELISA. An additional seven patients were positive only in the ELISA. Six of these were borderline positive, i.e., the posttreatment:pretreatment ratio was less than or equal to 5. The results of this study confirm that Intron A is minimally antigenic in human subjects.

Antibody Formation↗
PubMed1987

Treatment of Kaposi's sarcoma with interferon alfa-2b (Intron A).

The activity of the alpha interferons against AIDS-related Kaposi's sarcoma (KS) has been demonstrated in numerous clinical trials. Unfortunately, most reports have involved small patient cohorts and a variety of dosages and schedules of administration. We report here a series of Phase II trials with interferon alfa-2b (Intron A, Schering Corp., Kenilworth, NJ) involving 114 patients using three dose regimens. Patients received 50 X 10(6) IU/m2 intravenously (high dose), 30 X 10(6) IU/m2 subcutaneously (intermediate dose), or 1 X 10(6) IU/m2 subcutaneously (low dose). Clinical responses were seen in all regimens and, overall, 35% of the patients obtained complete or partial remissions. The response rates in the low-, intermediate-, and high-dose groups were 33%, 28%, and 45%, respectively. In addition, high-dose therapy was associated with more rapid time to response. Patients with low-stage (I or II) disease and those who lack B symptoms were more likely to respond to therapy; i.e., response rates for patients without B symptoms were 38%, 44%, and 60% in the low-, intermediate-, and high-dose groups, respectively. Seventy (61%) patients had died at the time of data collection, with a median survival of 15 months. Disease stage and the presence of B symptoms significantly affected mortality. Responders enjoyed significantly longer survival (P less than 0.10) than did nonresponders both overall and when adjusted for disease stage. Interferon alfa-2b was generally well tolerated, although almost all patients experienced flu-like symptoms. No life-threatening toxicities occurred and only six (6%) patients discontinued treatment due to adverse reactions. No significant improvement in immunologic parameters was detected during this study. These studies suggest that, in this disease setting, interferon alfa-2b may be acting through direct antiproliferative effects rather than as an immunomodulator, and higher doses appear to be more effective than very low doses.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Clinical overview of alpha interferon. Studies and future directions.

The clinical development of the alpha interferons has now progressed through initial Phase I and II trials into extensive controlled clinical trial designs. Alpha interferon has been a prototype of other biological agents that are now in clinical development. These agents operate through fundamentally different mechanisms of action than conventional chemotherapy and have produced a unique profile of side effects as well as response patterns. Time to response is generally longer than with chemotherapy, and dose-response and schedule-dependency questions continue to be explored for most tumor types. Although response rates have been low against most solid tumors when alpha interferon is used as a single agent, it has demonstrated a surprisingly wide range of efficacy in hematologic malignancies. These include tumors of presumed B-cell, T-cell, and myeloid lineages. In some diseases, e.g., hairy cell leukemia and chronic myelogenous leukemia, alpha interferon is broadly effective; it appears to considerably reduce or occasionally eliminate the malignant clone while normalizing the peripheral blood counts in most patients. In other diseases, alpha interferon appears destined to play a major role as part of combination therapy or in maintenance or consolidation therapy. In other disease settings, alpha interferon's role continues to be explored as part of combination therapy, adjuvant therapy, or as local-regional therapy. The full potential of alpha interferon as an antineoplastic agent will not be determined for many years. In this paper, the results from the first 5 years of widespread clinical testing are reviewed.

Antineoplastic Agents↗
PubMed1987

A finite-difference electromagnetic deposition/thermoregulatory model: comparison between theory and measurements.

The rate of the electromagnetic energy deposition and the resultant thermoregulatory response of a block model of a squirrel monkey exposed to plane-wave fields at 350 MHz were calculated using a finite-difference procedure. Noninvasive temperature measurements in live squirrel monkeys under similar exposure conditions were obtained using Vitek probes. Calculations exhibit reasonable correlation with the measured data, especially for the rise in colonic temperature.

Animals↗
PubMed1987

Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0 X 10(6) IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table. Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.

Acute Kidney Injury↗