High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation.

PURPOSE: Risk stratification of metastatic and relapsed Ewing's tumors (ETs) has been a matter of debate during the last decade. Patients with bone or bone marrow metastases or early or multiple relapses constitute the worst risk group in ET and have a poorer prognosis than patients with primary lung metastases or late relapses. In this article, the results of the present Meta European Intergroup Cooperative Ewing Sarcoma Study (MetaEICESS) (tandem melphalan/etoposide [TandemME]) were compared with the result of the previous study (hyper melphalan/etoposide [HyperME]), both at 5 years, in a patient population within the same high-risk stratum to determine toxicity. PATIENTS AND METHODS: Among 54 eligible patients, 26 were treated according to the HyperME protocol, and 28 were treated according to TandemME protocol. Patients received six cycles of the Cooperative Ewing Sarcoma Study treatment in HyperME and six cycles of the EICESS treatment in TandemME as induction chemotherapy. Patients also received involved-compartment irradiation for local intensification and myeloablative systemic intensification consolidation with hyperfractionated total-body irradiation (TBI) combined with melphalan/etoposide in HyperME or two times the melphalan/etoposide in TandemME followed by autologous stem-cell transplantation. RESULTS: The event-free survival (EFS) rate +/- SD in HyperME and TandemME was 22% +/- 8% and 29% +/- 9%, respectively. The dead of complication rate was 23% in HyperME and 4% in TandemME. CONCLUSION: TandemME offers a decent, albeit still not satisfactory, rate of long-term remissions in most advanced ETs (AETs), with short-term treatment and acceptable toxicity. TBI was not required to maintain EFS level in this setting but was associated with a high rate of toxic death. Future prospective studies in unselected patients are warranted to evaluate high-dose therapy in an unselected group of patients with AET.

Radiotherapy and high-dose chemotherapy in advanced Ewing's tumors.

BACKGROUND: Ewing's tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewing's tumors: Patients with primary multifocal bone disease, patients with early (< 2 years after diagnosis) or multifocal relapse. PATIENTS AND METHOD: As of 1987, 83 patients have been treated in the EICESS group, 39 of them at the transplant center in Düsseldorf, who have been analyzed here. All individuals received 4 courses of induction chemotherapy with EVAJA and stem cell collection after course 3 and 4. Consolidation radiotherapy of the involved bone compartments was administered in a hyperfractionated regimen 2 times 1.6 Gy per day, up to 22.4 Gy simultaneously to course 5 and 22.4 Gy to course 6 of chemotherapy. The myeloablative chemotherapy consisted of melphalan and etoposide (ME) in combination with 12 Gy TBI (Hyper-ME) or Double-ME with whole lung irradiation up to 18 Gy (without TBI). RESULTS: The survival probability at 40 months was 31% (44% DOD; 15% DOC). Pelvic infiltration did not reach prognostic relevance in this cohort. Radiotherapy encompassed 75% of the bone marrow at maximum (average 20%). Engraftment was not affected by radiotherapy. CONCLUSION: High-dose chemotherapy can improve outcome in poor prognostic advanced Ewing's tumors. The disease itself remains the main problem. The expected engraftment problems after intensive radiotherapy in large volumes of bone marrow can be overcome by stem cell reinfusion.

Effect of solution and suspension type aerosol of formoterol on tremor response and airways in patients with asthma.

BACKGROUND: Aerosol delivery and deposition to the oropharynx and the lungs have been found to be different for solution-type and suspension-type metered-dose aerosols used for treatment of asthma. We investigated possible differences in clinical effects between solution and suspension metered-dose formoterol aerosols. METHODS: A total of 24 patients with asthma (forced expiratory volume in 1 second, < or = 70% predicted) inhaled single doses (12 micrograms or 24 micrograms) of formoterol solution and suspension so that we could investigate the immediate tremor, airway, and cardiovascular responses in a randomized, double-blind, crossover trial. Fenoterol suspension aerosol (400 micrograms) was used for comparison (single-blind, poststudy, nonrandomized administration). Fenoterol (400 micrograms) as a rescue medication was inhaled after 120 minutes on each of the 5 study days. RESULTS: The order of mean (+/- SEM) maximum tremor acceleration was as follows: 12 micrograms formoterol solution (67.92 +/- 4.54 cm x sec-2) < 24 micrograms solution (73.46 +/- 4.51 cm x sec-2) < 12 micrograms suspension (80.87 +/- 5.08 cm x sec-2) < fenoterol (84.13 +/- 4.21 cm x sec-2) < 24 micrograms formoterol suspension 88.54 +/- 6.26 cm x sec-2). Maximum increase in specific airway conductance ranged from 0.48 +/ 0.03 to 0.55 +/- 0.04 sec-1 x kPa-1 for all drugs (p > 0.05). No change in cardiovascular parameters occurred (p > 0.05). CONCLUSION: No difference in the bronchial response to either formulation of formoterol was found. Tremor response to suspension aerosol (24 micrograms > 12 micrograms) was higher than that to solution aerosol (24 micrograms > 12 micrograms), indicating possible differences in systemic absorption because of a different deposition pattern. Rescue medication demonstrated systemic effects on tremor that were additive to those of formoterol.

Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic patients. Pharmacodynamic effects on beta 2-adrenergic receptors.

This study investigated the effects of an osmotic release oral drug delivery system of metoprolol on the changes induced by cumulative doses of inhaled salbutamol on bronchomotor tone, skeletal muscle, and the circulatory system after single (day 1) and multiple (day 7) dosing in 18 hypertensive asthmatic patients (forced expiratory volume in 1 second > 50% predicted; diastolic blood pressure > 90 mm Hg). The patients were given 14/190 mg metoprolol, 100 mg atenolol, and placebo once daily for a 7-day period each in a randomized, double-blind, crossover design. At the estimated time of peak plasma concentrations, cumulative doses of salbutamol (12.5, 37.5, 112.5, 412.5, 812.5, and 1612.5 micrograms) were applied every 20 minutes. Specific airway conductance, finger tremor amplitude, heart rate, and blood pressure were registered at baseline and at each dose increment. The slopes of the salbutamol dose-response curves of specific airway conductance did not differ on day 1 (P > .05). On day 7, atenolol caused a shift of the dose-response curves of specific airway conductance to the right (P < .05), whereas metoprolol was indistinguishable from placebo (P > .05). The median cumulative salbutamol concentrations causing a 50% increase in specific airway conductance were 416 and 384 micrograms (days 1 and 7, respectively) for placebo, 594 and 444 micrograms for metoprolol, and 562 and 1419 micrograms for atenolol. The median cumulative salbutamol concentrations causing a 35% increase in tremor were 732 and 706 micrograms for placebo, 812 and 1213 micrograms for metoprolol, and 797 and 1323 micrograms for atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the bronchodilator, tremorogenic, cardiovascular and hypokalaemic effects of fenoterol dry powder in asthma.

1. The airway and tremor response and cardiovascular and hypokalaemic effects of single and cumulative doses of fenoterol given by dry powder capsules (DPC) and by metered dose inhaler (MDI) were studied in asthmatics in two randomized, crossover trials. 2. Single doses of fenoterol DPC and MDI (0.2 mg, 0.4 mg), investigated in 24 subjects, produced similar, dose-dependent increases in FEV1. Fenoterol DPC caused less tremor response and less hypokalaemic effects than fenoterol MDI. 3. Cumulative doses of fenoterol DPC and MDI (0.2, 0.6, 1.4, 3.0, 6.2 mg), investigated in 12 subjects, produced a comparable bronchodilatation (mean maximum increase in FEV1 was 0.53 +/- 0.06/0.52 +/- 0.081 for DPC/MDI) and a similar, dose-dependent rise in heart rate (35 +/- 3.81/41 +/- 2.25 beats min(-1)). The rise in tremor and the fall in plasma potassium were smaller after DPC than after MDI. The mean maximum changes were 51.58 +/- 6.41/95.83 +/- 6.75 cm s(-2) for tremor and -0.68 +/- 0.09/-0.96 +/- 0.10 mmol l(-1) for potassium. 4. Our findings may result from a difference in the pharmacokinetics of the dry powder and the aerosol formulation, particularly differences in distribution and absorption. 5. In conclusion, fenoterol DPC used in low therapeutic doses (0.2,0.4 mg), is preferable to the MDI. Fenoterol DPC used as rescue medication in high cumulative doses, do not suggest a greater safety margin than the MDI and the same restrictions should be considered for the fenoterol dry powder formulation as suggested for the MDI.

Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma.

The airway and tremor response and cardiovascular and hypokalemic effects of single doses of inhalative fenoterol dry powder capsules (0.4 mg) were compared with the fenoterol metered dose inhaler (0.4 mg) and colforsin (forskolin) dry powder capsules (10.0 mg), a direct activator of the adenylate cyclase system, in 16 patients with asthma. Subjects (FEV1 < or = 60% predicted) were investigated in a randomized, double-masked, placebo-controlled, four-period, crossover trial for a 120 minute period. All active drugs caused a significant increase in specific airway conductance (p < 0.05); the order of potency (mean +/- SEM maximum increase from baseline) was fenoterol metered dose inhaler (0.51 +/- 0.06 sec-1 x kPa-1), fenoterol dry powder capsules (0.49 +/- 0.07), and colforsin dry powder capsules (0.30 +/- 0.03). A marked increase in finger tremor amplitude resulted after fenoterol metered dose inhaler only (62.93% +/- 10.21%; p < 0.05) in contrast to fenoterol dry powder capsules (15.84% +/- 4.35%; p < 0.05) and colforsin dry powder capsules (12.87% +/- 10.44%; p > 0.05). A decrease in plasma potassium was found after fenoterol (metered dose inhaler > dry powder capsules; p < 0.05). In conclusion, fenoterol dry powder capsules caused less tremor response and hypokalemic effects than the metered dose inhaler, although the bronchodilator capacity was similar. Colforsin dry powder capsules resulted in a measurable bronchodilatation in patients with asthma.

Double-blind randomized clinical trial on imidazole salicylate vs ibuprofen in osteoarthritis.

Imidazole salicylate (750 mg t.i.d.) was compared with ibuprofen (400 mg t.i.d.) in a 60-day double-blind parallel group clinical trial in 31 patients with osteoarthritis. Both drugs were effective in relieving joint pain and in reducing the duration of morning stiffness. A statistically significant reduction of the severity of these symptoms was observed already one week after the start of treatment, lasting until the end of the study. No significant differences in efficacy were demonstrated between the two drugs throughout the trial. The systemic tolerability, assessed by changes in tests of hematological, liver and kidney function, urinalysis and faecal occult blood was excellent with both treatments. The incidence of side effects (mostly gastrointestinal complaints) was fairly low in both groups, and less severe in the group treated with imidazole salicylate.

A three year comparative study of auranofin and gold sodium thiomalate in rheumatoid arthritis.

UNLABELLED: One hundred twenty-one patients with active RA were randomly assigned to receive 6 mg auranofin (AF)/day (60 patients) or 50 mg gold sodium thiomalate (GST)/week (62 patients) in a double-blind fashion. There were no intergroup differences with respect to sex, age, duration (median 2 years), stage and activity of the disease. In the case of "striking improvement" after 24 weeks a dose reduction to 50 mg GST/month or 4 mg AF/day was allowed and carried out in all GST patients and no AF patient. The serum gold levels were 5 times higher with weekly GST, they approached those of the AF group with monthly GST injections. The clinical parameters--number of swollen joints, activity index, articular index, grip strength, ESR--improved significantly in both groups, but grip strength, articular index and ESR improved more pronounced in the GST group. The X-ray progression (hands and forefeet) was significantly greater in the AF group. Forty-eight AF patients (80%) and 39 GST patients (36%) completed the first year. Thereafter the study was continued as an open study but the patients were allowed to switch from GST to AF. After the first and second year 14/7 GST patients switched to AF. The second/third year was completed by 37/22 AF pat. (62%/37%) and by 15/8 GST pat. (24%/13%). Skin reactions were more common with GST (41.9%/26.7%), diarrhoea was more common with AF (36.7%/19.4%), proteinuria occurred in 10% in both groups, leucopenia and thrombocytopenia were rare in both groups (1.7%). The withdrawal rate due to adverse events was 10%/26% in the AF/GST group during the first year (p less than 0.05) and 25%/32% over the three year period (n.s.). CONCLUSION: Both AF and GST are effective in the long-term treatment of RA, but GST is more so in radiological progression and ESR.

Auranofin and gold sodium thiomalate in the treatment of rheumatoid arthritis: a one-year, double-blind, comparative multicenter study.

In a 48-week, double-blind trial, 122 patients were randomly assigned to treatment with auranofin (60) and gold sodium thiomalate (GST) (62) at five centers. Both groups showed significant improvement (P less than 0.05) from baseline in parameters of disease activity. Results of the covariance analysis for all patients who completed the trial showed no significant differences (P less than 0.05) in efficacy between the two groups. The proportions of patients showing 50% or greater improvement in tender joints, swollen joints, activity index, severity of pain, general health rating, and erythrocyte sedimentation rate (ESR) were similar for both auranofin-treated and GST-treated patients who completed the 48-week trial. When all patients who entered the trial were evaluated, a slightly greater proportion of patients on auranofin had improved. Diarrhea occurred more frequently with auranofin (32%) compared to GST (19%), whereas rash and pruritus were twice as common in those patients treated with GST compared to those treated with auranofin. The withdrawal rate due to adverse reactions was 10% for auranofin vs 26% for GST. It was concluded that the efficacy of auranofin was comparable to that of injectable gold and was better tolerated, as evidenced by the lower withdrawal rate from adverse events for the auranofin patients.

[Multicenter double-blind comparison of auranofin and Tauredon]. / Multizentrischer Doppelblindvergleich zwischen Auranofin und Tauredon.

A multicenter double-blind comparative study with auranofin (Ridaura) and Na-auro-thiomalate (Tauredon) was carried out in order to investigate under controlled conditions whether the new oral gold compound may be an alternative to injections of gold salts. 121 patients were included in the study, data of 86 patients treated for at least one year could be analysed. The following parameters were examined at regular intervals: number of painful and swollen joints, grip strength, morning stiffness, pain and general health on the visual analogue scale, ESR; from these data the articular index and activity index (according to Lansbury, with slight modifications) were calculated. Blood samples for routine safety monitoring and serum gold levels as well as urine tests were obtained regularly. Both treatment groups showed similar improvement in the values for efficacy measurements after one year, starting within 8 to 12 weeks. Patients in the auranofin group with a disease duration of less than 2 years showed greater improvement in the values for efficacy assessment with the exception of grip strength and the number of tender joints than patients with a disease duration of 2 years or more. No such trend was seen in the Tauredon-subgroups. Numerous side effects were recorded in both groups: 89.7% of the patients on Tauredon and 68.8% of the patients on auranofin had observed one symptom during the course of one year. There was a clear distinction concerning the nature of side effects: mucocutaneous symptoms, especially rash and pruritus, were approximately twice as common with Tauredon, whereas diarrhoea was much more frequent in patients treated with auranofin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Interaction between fibronectin and aggregated IgG]. / Wechselwirkungen zwischen Fibronectin und aggregiertem IgG.

The present study shows that plasma fibronectin forms complexes with aggregated human IgG (a model for immune complexes) and that the resulting complexes precipitate spontaneously or after addition of PEG from buffered saline. However, no clearcut interaction was observed in serum or synovial fluid. Two currently-used immune complex assays, the C1q solid phase assay and the conglutinin binding assay in a commercial inhibition variant, were tested as to their reliability in the presence of fibronectin. While the C1q-dependent assay showed low susceptibility to fibronectin, the conglutinin binding assay gave increased immune complex values in the presence of pathological concentrations of fibronectin.

Auranofin and sodium aurothiomalate in the treatment of rheumatoid arthritis. A double-blind, comparative multicenter study.

Auranofin (AF), a new gold compound, has been suggested as an alternative to parenteral gold in the treatment of rheumatoid arthritis (RA). This hypothesis has been tested within a double-blind comparative study and to date 103 patients have been enrolled. Forty-one RA patients have been treated for longer than 6 months. The patients were randomly allocated to treatment with either AF or sodium aurothiomalate (GSTM) and serial comparison of changes within the articular index, grip strength, pain, morning stiffness, and global assessment during treatment were measured. Improvement was noted within both treatment groups. Diarrhea as a side effect was most commonly seen during treatment with AF while rash often combined with pruritus was most commonly reported with GSTM; withdrawal from treatment as the result of this was nevertheless uncommon.

[Clinical pharmacological trials of a new metered dose inhaler, IK-6, a combination of the bronchodilators fenoterol and ipratropium bromide (author's transl)]. / Klinisch-pharmakologische Untersuchungen mit dem IK-6-Dosieraerosol, einer Kombination der Bronchospasmolytika Fenoterol und Ipratropiumbromid.

IK-6, a combination of the sympathomimetic fenoterol (low dose) and the anticholinergic ipratropium bromide (normal dose), was tested single-blind and cross-over in outpatients with intrinsic asthma and in healthy volunteers. In 12 patients IK-6 resulted in a good acute bronchodilatation, the onset was as quick as following fenoterol and the maximum was as good as following ipratropium bromide. In another 12 patients the protective effect against an acetylcholine-induced bronchoconstriction was better after IK-6 than after ipratropium bromide and much better than after salbutamol. In these patients IK-6 caused no unwanted side effects. In 10 healthy volunteers the effect on heart rate was tested after inhalation of 20 puffs of bronchodilators applied by metered dose inhaler. The anticholinergics (ipratropium bromide, oxitropium bromide, dibenzothiepine-derivative) caused no effect. Following fenoterol a marked increase in heart rate could be observed, whereas the combination IK-6 caused only a slight increase.

[Indometacin glucosamide in the therapy of rheumatoid arthritis (author's transl)]. / Indometacin-glucosamid in der Behandlung der chronischen polyarthritis.

40 patients with classical or definite rheumatoid arthritis were included in a double blind trial to assess efficacy and side effects of indometacin (n = 20) versus glucametacin (n = 20). In a daily dose of 420 mg glucametacin proved to be equally potent to 150 mg indometacin daily in its anti-inflammatory activity but showed fewer side effects.

Clinical studies of the interaction between tolmetin and glibenclamide.

Forty patients with diabetes mellitus and rheumatic disorders (rheumatoid arthritis, osteoarthritis, soft-tissue rheumatism) were included in a double-blind trial with the purpose of investigating whether the concomitant administration of tolmetin and glibenclamide leads to an interaction. No significant alterations of blood and urine glucose values could be found in comparison to placebo. Therefore it can be assumed that there is no interaction between these two substances.