Correlation of clinical and serological findings in patients with rheumatoid arthritis treated for one year with interferon-gamma.

Results of a large therapeutic trial of interferon-gamma in patients with rheumatoid arthritis (RA) are described. Of 110 RA-patients enrolled in this clinical trial, 46 were treated with interferon-gamma for 12 months. During the treatment period, dosage was reduced on an individual basis. There was a correlation between the improvement of clinical parameters, such as pain or morning stiffness, and the improvement of laboratory parameters such as erythrocyte sedimentation rate, anemia, leucocytosis or thrombocytosis. Interferon-gamma was well tolerated, and no organ toxicity was detected.

[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.

Results of a multicenter placebo-controlled double-blind randomized phase III clinical study of treatment of rheumatoid arthritis with recombinant interferon-gamma.

In a multicenter placebo-controlled double-blind randomized clinical study, 91 patients with rheumatoid arthritis were given 28 days' treatment with recombinant interferon-gamma (50 micrograms daily for 20 days, then 50 micrograms each second day up to day 28, given by subcutaneous injection). The aim of the study was to provide a methodologically clear demonstration of the efficacy of treatment with interferon-gamma, using criteria that could be handled by statistical tests. Evaluatable documentation was available for 79 patients, of whom 40 were treated with the active compound. The principal criterion for the statistical evaluation of the therapeutic success was improvement of the Ritchie "joint pain index" or Lansbury "joint pain index" by at least 30% within 28 days. The chi-square test showed superiority of the interferon arm over the placebo arm with an error probability of alpha less than 1%. In addition, efficacy of interferon-gamma was demonstrated in respect of practically all parameters investigated. The frequency of side-effects, including febrile reactions, was the same for the active compound and the placebo. During interferon treatment the daily maximum body temperature was raised by 0.3 degrees C on average, but was below 37.2 degrees C at all times.

[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.

Results of a phase-II clinical trial on treatment of rheumatoid arthritis with recombinant interferon-gamma.

In an open, non-randomized clinical trial conducted at multiple centres, 49 patients with rheumatoid arthritis were treated with recombinant interferon-gamma for 20 days. The study was carried out in two sub-studies. In the first, the total daily dose of interferon-gamma was 50 micrograms; in the second, 100 micrograms. Of the 49 cases, 40 were evaluable for statistical analysis; 24 of these patients (60%) responded to therapy, according to the criteria of a successful outcome laid down in the study protocol, and were classified as responders. In responders, the clinical parameters investigated improved with both dosages. The lower dosage differed from the higher one in having a markedly lower incidence of side-effects. The results lead to the conclusion that a randomized double-blind phase-III clinical trial should be performed.

[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.

[Interferon in chronic polyarthritis. Positive effect in clinical evaluation]. / Interferon bei chronischer Polyarthritis. Positive Wirkung in der klinischen Prüfung.

During the last two years, 80 patients with definite chronic rheumatoid arthritis were treated with interferon-gamma. Considerable improvement in the clinical picture occurred in 58, with pain decreasing rapidly and lastingly or even disappearing. Even in largely immobile patients the ability to walk and general mobility were nearly fully restored. The treatment was well tolerated in 74 patients. As the substance is administered subcutaneously it is suitable for out-patient treatment.

Platelet-adjusted IFN dosage in the treatment of advanced hairy cell leukemia.

It has been demonstrated that hairy cell leukemia (HCL) can be efficiently treated by various preparations of alpha interferons (IFN). Nevertheless, there are several open questions, such as the route, mode and dosage of IFN application. These variables of IFN treatment may be critical since a myelosuppressive effect of IFN, which is commonly seen in the initial phase of treatment, can result in further deterioration of the already impaired platelet production in advanced HCL. The present study shows that serious side effects can be avoided and the flu-like syndromes described by others almost completely reduced by s.c. application of IFN via a portable pump during a daily 8 h period. IFN is initially given five times a week and the daily dose is adjusted according to the actual platelet count. The efficiency controls show that the increase of platelets in the peripheral blood, which is most critical in advanced HCL, may be seen earlier by this than by other protocols, which usually recommend higher daily doses of IFN and only three instead of five weekly applications.

[Improved clinical course of herpes zoster in immunosuppressed patients treated with fibroblast interferon]. / Günstigerer Verlauf des Herpes zoster bei immunsupprimierten Patienten unter Behandlung mit Fibroblasteninterferon.

In a randomized study with patients suffering from herpes zoster spread of eruptions was inhibited and segmental pain was reduced rapidly by continuous infusion of daily 0.5 X 10(6) IE fibroblast interferon/kg body weight for 3-5 days. Postherpetic neuralgia was observed more rarely and interferon healing of eruptions was accelerated by interferon compared to the controls.

[Electronmicroscopic studies on the skin pigmentation of the red bellied toad Bombina bombina (L.)]. / Elektronenmikroskopische Untersuchungen zur Hautpigmentierung der Rotbauchunke, Bombina bombina (L.).

The various colours of the red-bellied toad Bombina bombina are caused by 3 types of chromatophores, the red xanthophores, the white iridophores and the black melanophores. In the brownish skin and in the black spots of the dorsal region all types of chromatophores are found. But in the epidermis of the black spots there are more grana of melanin than in the other region of the back. The 3 types of chromatophores are not present in the skin of all parts of the body. The dark blue colour of the belly is caused only by melanophores, whereas in the ventral parts with light blue colour there occur melanophores and iridophores. The white spots of the belly contain only iridophores, the red spots have iridophores and xanthophores.

[Glands in the skin of the fire-bellied toad (Bombina bombina(L.); Discoglossidae, Anura): type, number, size and distribution under natural and experimental conditions]. / Die Drüsen in der Haut der Rotbauchunke (Bombina bombina(L.); Discoglossidae, Anura): Art, Anzahl, Grösse und Verteilung unter natürlichen und experimentellen Bedingungen.

1. In the skin of the fire-bellied toad (Bombina bombina) 5 types of glands are found. By analogy with the comparable glands of the yellow-bellied toad and the grass frog, these are called the toxic, lumpy, mucous, callous, and small glands. The callous glands were omitted from the present study. 2. Lumpy glands are most numerous in the middle of the back of the fire-bellied toad, their numbers decreasing progressively over the sides to the middle of the ventral surface. Mucous glands are more common cranially than caudally. The toxic and small glands are uniformly distributed over the body. 3. On the average there are 700 glands per square cm of skin in the fire-bellied toad. Of these, in the male the lumpy glands represent less than 10%, while the toxic, mucous and small glands each account for 30%. In the females 50% of the total number of glands are mucous glands, and only about 10% toxic glands; lumpy and small glands occur in the same proportions as in the males. Following gonadotropin injection, no change in the number of glands was observed in the male. 4. The largest toxic and lumpy glands are located cranially; toward the tail their size is reduced. The mucous glands have the greatest volume on the sides of the body. Small glands are of similar size everywhere. 5. Glands of uniform size are arranged in longitudinal rows on this toad. The dorsally situated toxic, lumpy and mucous glands are larger, on the whole, than the more ventral glands of the same types. 6. All 4 gland types on the body of Bombina are larger in males than in females. 7. Following administration of PMS to the male there is a selective increase in volume of the toxic and lumpy glands on the dorsal surface, but no corresponding increase on the ventral surface. Mucous and small glands do not change in size after hormone treatment. 8. The capacity of all the glands in a cm2 of skin, in terms of mean volume, is 1.7 mm3 in males not treated with hormones. After PMS treatment of the male the gland volume per cm2 increase to 2.5 mm3. The total volume per cm2 in females is only 0.65 mm3.

Fat and glycogen utilization in the larynx Muscles of fire-bellied toads (Bombina bombina L.) during calling activity.

Both fat and glycogen are present in abundance in the larynx muscles of anurans. To clarify their role, the Musculus dilatator laryngis of the male fire-bellied toad, Bombina bombina was studied. In untreated males, the mean fat content of this larynx muscle was 14%; the muscle contained glycogen amounting to 57% of that measured in the liver tissue of the same animal. After thirteen days of continual calling activity induced by administration of a gonadotropin, the fat content fell to 6%, the glycogen to 34%. The fat content was essentially unchanged (13%) by four hours of electrical stimulation of the muscle; the glycogen content, however, had fallen to 42% after this treatment. Neither component was altered in amount by castration, the fat content being about 13% and that of glycogen, 52%. Nor did treatment with gonadotropic hormone reduce either the fat content (13%) or the amount of glycogen (59%). From these results it was concluded that fats represent a direct source of energy for the larynx muscles, which is used up gradually over long periods of calling. The glycogen in these muscles, on the other hand, is a short-term store sufficient to supply energy for only a few hours of calling activity.

[Spermatogenesis in the yellow-bellied toad (Bombina variegata variegata L.) during the seasonal activity period and in correlation with the mating call activity (Discoglossidae, Anura)]. / Die Spermatogenese bei der Gelbbauchunke (Bombina variegata variegata L.) im Verlauf der jährlichen Aktivitätsperiode und die Korrelation zur Paarungsrufaktivität (Discoglossidae, Anura).

The spermatogenic tissue in the yellow-bellied toad Bombina variegata has certain properties not shared by other Central European anurans. Sertoli cells are lacking; the sperms are not bundled within the seminiferous tubules, but rather they form and mature in a connective-tissue follicle that is cellular in nature. Spermatogenesis is not a continuous process, at either the spermatocyte or the spermatozoa formation stage. Rather, there are periods of stagnation and of proliferation, which can be correlated with the periods during which the male toads produce mating calls and with the pauses between the calling periods. The crucial participation of hormonal factors in these processes is discussed.