Recombinant interferon beta gel as an adjuvant in the treatment of recurrent genital warts: results of a placebo-controlled double-blind study in 120 patients.

BACKGROUND: Pilot studies of adjuvant therapy with topically applied interferons (IFN) have shown promising results in reducing the recurrence of condylomata acuminata (CA). OBJECTIVE: The aim of this multicenter placebo-controlled, double-blind study was to confirm the efficacy and safety of topically applied IFN in a large sample of patients. METHODS: After removal of CA by CO2 laser surgery, electrocautery or cryosurgery, 120 patients applied either recombinant IFN-beta (0.15 or 1.0 x 10(6) IU/g) or placebo gel to the affected areas 5 times daily for 4 weeks. The patients were followed for a total of 24 weeks or until recurrence of CA was observed, respectively. RESULTS: In the 105 patients evaluated for efficacy after 24 weeks, recurrence rates were 75% (27/36 patients) in the placebo group, 62% (21/34) in the 1.0 x 10(6) IU/g group (n.s.) and 54% (19/35) in the 0.15 x 10(6) IU/g group (p = 0.034). Only few mild adverse events were noted, which were almost limited to the application site. CONCLUSION: Topical application of gel containing 0.15 x 10(6) IU/g recombinant IFN-beta is safe and appears to reduce the recurrence of CA after surgical treatment.

Pharmacodynamics of recombinant IFN-beta during long-term treatment of malignant melanoma.

The pharmacodynamics and biologic activities of recombinant human interferon-beta (rHuIFN-beta) derived from chinese hamster ovary (CHO) cells were examined during long-term therapy in 7 melanoma patients. The CHO-derived rHuIFN-beta was given s.c. in a dose of 3 x 10(6) U three times per week for 24 weeks. Serum levels of IFN could not be detected before and 48 h after the s.c. injections. 2'-5'-Oligoadenylate synthetase (2-5 OAS), beta 2-microglobulin, and neopterin levels increased significantly 48 h after application, with a maximum after 96 h. Subsequently, the values decreased and remained only slightly elevated during the long-term therapy. Natural killer (NK) cell activity increased in the first 96 h significantly and fell below pretreatment values after 4 weeks. The decrease of biologic response could not be attributed to the occurrence of anti-IFN-beta antibodies because only 2 of the 7 patients developed neutralizing antibodies after 16 and 24 weeks of treatment, respectively. This trial confirms the biologic potency of CHO-derived rHuIFN-beta. However, the selected parameters demonstrate that immunostimulation is only possible over a short treatment period.

Low-dose natural interleukin-2 and recombinant interferon-gamma following autologous bone marrow grafts in pediatric patients with high-risk acute leukemia.

Twenty-two patients with high risk hematologic malignancies (13 c-ALL, two B-ALL/NHL, four T-ALL, two AML M2, one pre-pre B-ALL) entered a phase I/II trial with cyclic administration of low dose natural interleukin-2/recombinant interferon-gamma (nIL-2/rIFN-gamma) following autologous bone marrow transplantation (ABMT), in order to induce a cytotoxic antileukemic effect. Eighteen patients subsequently relapsed, corresponding to a Kaplan-Meier estimate of disease-free survival (DFS) of 18%. Compared with a historical group of autologous bone marrow recipients who have not received immunotherapy, there is no significant difference according to DFS. Immunophenotyping of peripheral lymphocytes at the onset and end of therapy cycles revealed the most significant mean increase among the NK cell population (262/microliters +/- 51 vs. 354/microliters +/- 36, p = 0.004). However, even CD3 positive T cells rose significantly (591/microliters vs. 689/microliters, p = 0.04). In vitro NK cell activity tested against the NK sensitive myeloid leukemic cell line K562, and LAK cell activity tested against the LAK sensitive Burkitt lymphoma cell line Raji, was only low. An additional in vitro stimulus with nIL2, however, led to a therapy-dependent increase of cytotoxicity which was significant against Raji cells (25% +/- 4 vs. 41% +/- 5, p = 0.0124) indicating that low dose nIL2/rIFN-gamma enhances precursors of potentially cytotoxic cells in vivo.

Short term treatment of visceral leishmaniasis of the Old World with low dose interferon gamma and pentavalent antimony.

Eight adult patients with visceral leishmaniasis acquired in mediterranean countries were treated in a prospective study with a combined immunomodulating and antiparasitic regimen consisting of low-dose interferon-gamma (IFN-gamma) and pentavalent antimony. The clinical outcome, hematological and parasitological parameters, the duration of treatment and number of treatment cycles as well as the cumulative dose of pentavalent antimony applied, have been evaluated. The combined treatment led to complete resolution of symptoms and parasitological cure in all cases of visceral leishmaniasis without major side effects. Combined treatment resulted in a significant reduction of duration of treatment (19 vs. 31 days, p < 0.02) and cumulative dose of pentavalent antimony (11.67 vs. 19.30 g, p < 0.02) compared to historical controls (n = 6). No relapses occurred after a median follow-up of 9 months (range: 2-28 months). We conclude that combination therapy is tolerated well and is highly effective in patients with visceral leishmaniasis. The addition of IFN-gamma to standard therapy with pentavalent antimony may reduce the cumulative dose of antimonial drugs, shortens the treatment period and probably reduces the number of relapses.

Systemic interferon gamma treatment in severe atopic dermatitis.

BACKGROUND: Recent results suggest decreased interferon gamma (IFN-gamma) but high interleukin 4 (IL-4) production in patients with atopic dermatitis (AD). Because the relative activities of IL-4 and IFN-gamma seem to regulate the amplitude of the IgE response we suggested a role for IFN-gamma in the treatment of AD. OBJECTIVE: The purpose of this study was to assess the efficacy of systemic IFN-gamma treatment in patients with severe AD. METHODS: Patients with severe AD (n = 14) were treated with recombinant IFN-gamma for 6 weeks. During the study only basic local therapy with steroid-free hydrophilic or emollient ointments was allowed. RESULTS: Eight patients (57%) showed marked clinical improvement during systemic IFN-gamma therapy. Four of these patients showed continuous improvement 3 months after treatment was discontinued. Mean total and antigen-specific serum IgE concentrations were not statistically different during and after treatment, whereas mean spontaneous IgE production in vitro was significantly lower after 6 weeks of IFN-gamma therapy. CONCLUSION: Our results suggest that IFN-gamma treatment may represent a novel therapeutic approach in patients with severe AD.

[Bowenoid actinic keratosis: therapy with intralesional injection of recombinant beta-interferon]. / Bowenoide aktinische Keratose: Therapie durch intraläsionale Injektion von rekombinantem beta-Interferon.

Biopsy-proven bowenoid actinic keratosis located in the pretibial region in each of two elderly women (61 and 81 years) were treated with intralesional injections with a new recombinant beta-interferon. The treatment took the form of intralesional injections three times a week over 3 consecutive weeks. The dose per single injection was 1.5 or 1.0 MU interferon, respectively. Clinical and histological examinations showed a complete response in both patients. Controls up to 18 months showed no relapse. There were no flu-like side-effects. Leukocyte counts decreased by 2700 and 500 cells per microliter during therapy.

[Interferon gamma in the treatment of chronic polyarthritis. Long-term therapy in clinical practice]. / Interferon gamma in der Therapie der chronischen Polyarthritis. Die Langzeitbehandlung in der Praxis.

Efficacy and practicability of a defined dosage scheme for interferon gamma was proved during one year's treatment in patients with rheumatoid arthritis. Interferon gamma was well tolerated. It was effective in improving blood sedimentation rate, anemia, leucocytosis and thrombocytosis as well as clinical parameters such as pain, mobility, swollen joints and morning stiffness. Concomitant medication with corticosteroids could be reduced.

Therapy for systemic juvenile rheumatoid arthritis with gamma-interferon: a pilot study of nine patients.

Nine severely ill patients with a confirmed diagnosis of systemic juvenile rheumatoid arthritis were treated with recombinant gamma-interferon (gamma-IFN) in addition to the therapy they were previously receiving for their disease. Improvements in clinical symptoms were noted in 7 of the patients, and median laboratory values also showed a marked improvement after gamma-IFN treatment. A relapse occurred in 1 patient. The results of this study should stimulate further research on the use of gamma-IFN in systemic juvenile rheumatoid arthritis, particularly in determining the appropriate effective dosage.

[Interferon gamma: a Janus-faced mediator in inflammation]. / Interferon gamma: ein janusköpfiger Mediator bei Entzündungen.

A survey is given of the immunomodulatory effects of interferon gamma (IFN-gamma) in inflammation. IFN-gamma influences the activity of macrophages, granulocytes, B-lymphocytes, suppressor-T-lymphocytes and natural killer cells as well as the production of prostaglandins and leukotrienes, bone resorption, collagen synthesis and expression of HLA class II antigens. Furthermore, the production of IFN-gamma in patients with chronic inflammatory diseases is described as well as the recent in vivo investigations concerning induction and inhibition of inflammation by IFN-gamma. Based on these investigations a hypothesis is presented which offers an explanation for the contradictory results concerning the effects of IFN-gamma in inflammation. According to this hypothesis IFN-gamma takes part in the elicitation of an inflammatory reaction. As soon as a high inflammation activity is reached the reaction is inhibited via a negative feedback. Therefore, exogenously applied IFN-gamma has a stimulating effect if inflammation activity is low. In contrary, IFN-gamma inhibits this reaction if activity is high. The consequences resulting from this dual mode of action for the treatment of different diseases with IFN-gamma are discussed.

[Interferon-gamma in the therapy of chronic polyarthritis]. / Interferon-gamma in der Therapie der chronischen Polyarthritis.

The paper gives a survey of the studies with interferon-gamma and the actual status of the clinical trials with this substance concerning rheumatoid arthritis (RA). About 60% of the patients with RA respond to the therapy. In the initial therapy which covers a time of 2 to 6 weeks 50 micrograms (in case of side effects 20 or 10 micrograms) should be given 3 to 7 times per week by the subcutaneous route. When the disease is improved, the maintenance therapy starts. According to the patient's status, the dosage frequency and the dose have to be reduced to sustain the effect.

Changes in myelin sheath thickness and internode geometry in the rabbit phrenic nerve during growth.

The rabbit phrenic nerve was studied at seven phases of growth from the newborn to the adult to determine the length of the nerve fibres, the length of the internodes, the fibre calibre, the geometric proportions of the internodes and the thickness of the myelin sheaths. The elongation of the internodes corresponded precisely to the elongation of the nerve, indicating a constant number of approximately 140 internodes per fibre, each internode elongating commensurate with body growth. Internode elongation was accompanied by increases in fibre calibre, but these parameters did not change in precise proportion. The internodes of thick fibres were relatively short for calibre, as defined by the length/diameter quotient. This trend of foreshortening changed during growth. Sheath thickness, defined by the quotient axon diameter/fibre diameter, was determined with a computer-assisted method. Fibres of young rabbits had relatively thin sheaths for axon calibre, compared with adult rabbits. The changes in sheath thickness corresponded to the changes in internode geometry. This was consistent with previous studies showing that elongation or foreshortening of an internode of a given calibre has a slight, but definite effect on the thickness of its myelin sheath.

Amplitude, latency, and habituation of the electrodermal response to acoustic stimuli in the frog.

The electrodermal response (EDR) of frogs to various acoustic stimuli was measured in the form of the skin potential response (SPR). There was no correlation between the polarity of the SPR and the intensity of the stimuli. When different frequencies were presented at the same intensity, the amplitude of the SPR to each was inversely proportional to the sound pressure at which that frequency just elicited an SPR. The amplitude of the sound-induced SPR increased monotonically with increasing sound pressure. The latency of the SPR decreased with increasing intensity of the acoustic stimulus. Acoustic stimuli repeated at intervals of 1 and 2 min elicited responses with progressively decreased amplitude and increased latency; with 4 min intervals there was little habituation. Fatigue participates to only a very slight extent in reducing the amplitude of the SPR and increasing its latency. The results are compared with the published data on frogs and mammals, including humans.

Vocal response of male European water frogs (Rana Esculenta complex) to mating and territorial calls.

The responses of male European water frogs (the two species Rana lessonae and Rana ridibunda and their hybrid, Rana esculenta) to playback of their mating and territorial calls were studied during the mating season. In order to select biologically relevant intensities for the presentation of the recorded calls, the sound pressure of the calls produced by the frogs themselves was established prior to the experiment. At a distance of 1 m the most intense calls were those of R. ridibunda, with a sound pressure of 110 dB (peak SPL). The smaller males of R. esculenta gave calls about 5 dB lower in intensity. The calls of R. lessonae, the smallest phenotype, were still less intense, 10 dB lower than those of R. ridibunda. The territorial calls of all three phenotypes elicited territorial calls in all of the males tested, as a rule accompanied by approach to the sound source. The sound pressure required to elicit a vocal response was nearly the same for each of the three different territorial calls. Sometimes encounter calls and warning calls were given in addition to territorial calls. When the mating calls were presented at low intensity, in some cases the males responded with their own mating calls. Mating calls at higher intensity elicited the same behavior that appeared following presentation of territorial calls, but significantly higher sound pressures were required to elicit such a response to mating calls than to territorial calls. The males of R. lessonae and R. esculenta did not respond to the mating calls of R. ridibunda, and each of them had significantly lower thresholds to the mating call of its own phenotype than to that of the other. The males of R. ridibunda responded only to conspecific mating calls. The vocal-response thresholds are compared with those of the electrodermal response reacting to the same stimuli. The significance of the different calls of the European water frogs is discussed.

Quantitative studies on the elicitation of the electrodermal response by calls and synthetic acoustical stimuli in Rana Lessonae camerano, Rana R. Ridibunda pallas and the hybrid Rana "Esculenta" L. (Anura, Amphibia).

The thresholds of the electrodermal response (EDR) were determined for the European water frogs Rana lessonae, Rana ridibunda ridibunda, and their hybrid, Rana "esculenta". Both males and females were tested, during and outside the calling period. The stimuli used were the mating, territorial and release calls of all three phenotypes, as well as synthetic acoustical stimuli having the same impulse pattern but differing in frequency. The EDR could be elicited by all the calls tested, and by the synthetic acoustical stimuli at frequencies between 100 and 4000 Hz. Below ca. 1000 Hz the thresholds of the smaller Rana lessonae were higher than those of the bigger Rana ridibunda, while the relations were reversed above 1000 Hz. During the calling period the highest thresholds, in all three phenotypes, were those to the conspecific mating call. The synthetic stimulus at the dominant frequency of the mating call elicited the EDR only at sound pressures considerably higher than those of an effective synthetic stimulus at the dominant frequency of the territorial call. The thresholds to the territorial and release calls during the calling period were only slightly different from those at other times. Those to the mating call and to the synthetic stimulus at the dominant frequency of the mating call, however, were significantly lower than during the calling period. For each phenotype, the stimulus exhibiting the greatest seasonal fluctuation in threshold was the conspecific mating call.