Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea.

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

Multicentre study on intensified remission induction therapy for acute myeloid leukemia.

In a cooperative study at 13 centres in the Federal Republic of Germany, 213 adult patients with AML were treated for remission induction by a 9-day regimen consisting of cytosine arabinoside, daunorubicin and thioguanine (TAD) according to previously described sequencing. Complete remission was achieved in 70% of all patients. Complete remission rate was 57% in the 49 patients 60 years of age and older and 74% in the 164 patients under 60 years. Sixty-eight per cent of all complete remissions and 75% of those in the higher age group were induced by one induction course. Median survival was 10 months for all patients treated and 16 months for responders. Median remission duration was 13 months with 72 patients still in continuous remission for 1-31 months. Remission duration was not significantly different for patients treated either by monthly maintenance therapy or induction type consolidation without further therapy. However, patients completing two consolidation courses had a significantly longer remission duration of 22 months. Compared to similar multicentre studies on AML therapy the intensified induction regimen applied in this study shows an improvement even in older patients.

Pharmacodynamic comparison of L-bunolol with propranolol, metoprolol, and placebo.

Twelve healthy volunteers received single oral doses of propranolol (80 mg), metoprolol (100 mg), L-bunolol (2 mg), and placebo in a four-way crossover study. Blood pressure, ventricular rate, and echocardiographically determined ejection fraction, ejection time, and mean rate of circumferential fiber shortening (mVcf) were measured before dosing and at multiple time points during 10 hours after each dose, with subjects maintained in the supine position. Reductions in systolic and diastolic blood pressure following administration of each of the beta blockers were greater than those observed with placebo, but differences among the four treatments were not significant. Heart rate reductions with the beta blockers differed significantly from placebo (P less than .001), but differences among the three beta blockers were not significant. Differences among the four treatments in mVcf decrement did not attain significance at the 5% level (.05 less than P less than .1), and there were no significant differences in ejection-time prolongation or ejection-fraction reduction. Thus, reduced blood pressure, heart rate slowing, and reduced cardiac contractility may be associated with placebo treatment and may indicate the need for placebo controls in studies of the cardiovascular effects of beta blockers. Despite differing secondary pharmacologic properties, the three beta blockers reduced heart rate to a similar extent. Other effects of the beta blockers on blood pressure and cardiac contractility could not be consistently distinguished from those associated with placebo.

Reduced systemic absorption of intrabronchial lidocaine by high-frequency nebulization.

Serum lidocaine concentrations were measured in a series of patients during and after topical administration of lidocaine used to anesthetize the nasal mucosa, pharynx, and larynx for diagnostic fiberoptic bronchoscopy. In one group of patients (N = 9) the trachea and bronchi were sprayed with a 2% lidocaine solution administered in 2 mL volumes. Another group (N = 14) received a 2% lidocaine solution which was administered by inhalation of lidocaine dispensed by a high-frequency nebulizer. Multiple serum samples drawn over a 1-hour period were analyzed by gas chromatography with nitrogen-phosphorous detection. In the spray group versus the inhalation group, there were no differences in mean age (54 vs 55 years), total lidocaine dose (572 vs 525 mg), or time of peak serum lidocaine concentration (43 vs 41 minutes after dose). However, the peak serum lidocaine concentrations were significantly lower in the inhalation group vs the spray group (1.40 vs 3.63 micrograms/mL). Thus, administration of lidocaine via inhalation by ultrasonic nebulization results in lower peak serum concentrations, and a reduction in the likelihood of toxicity, than when administered by conventional topical spray.

[Hematopoietic stimulation for enhanced bone marrow regeneration after chemotherapy (author's transl)]. / Stimulation der Hämatopoese zur Beschleunigung der Regeneration nach zytostatisch bedingter Knochenmarksdepression.

The aggressivity of cancer chemotherapy is limited by hematologic side effects or makes expensive supportive therapy necessary. This article summarizes known and clinically usable methods of stimulating hematopoiesis to enhance bone marrow recovery after therapy. Longest known is the stimulatory effect of anabolic steroids, which may accelerate the regeneration of granulopoiesis and erythropoiesis. Lithium increases CSA-levels and enhances the regeneration of granulopoiesis and questionably thrombopoiesis according to several publications. The stem cell shift by hypertransfusion promotes granulopoiesis. As malnutrition limits hematopoietic recovery, optimal nutrition after chemotherapy should favor maximal hematopoiesis. Further studies are necessary before the application of the above mentioned methods to stimulate bone marrow - singly or in combination - can be recommended.

[Studies of lysozyme activity in serum, urine and blood smears from patients with haematological diseases]. / Untersuchungen der Lysozymaktivität in Serum, Urin und Blutausstrichen von Patienten mit hämatologischen Erkrankungen.

Lysozyme activity was studied in blood smears, serum, and urine of patients suffering from leukaemia or other haematological diseases. Increased enzyme activity was found in myelocytic, myelomonocytic and monocytic leukaemia and equally in secondary granulocytosis and polycythaemia vera. Reduced rates were found in lymphocytie leukaemia, malignant lymphoma with bone marrow involvement, and myelophthisic conditions. A rise in urinary lysozyme occurred when the serum level exceeded 50 microgram/ml. Abundant activities were found in myelomonocytic and monocytic leukaemias. Using the bacteriolytic method in blood smears, no enzyme activity was demonstrated in cells of acute or chronic lymphocytic leukaemia, in monocytic leukaemia however, almost all cells show strong reaction. In acute myelocytic or myelomonocytic leukaemia, the portion of positive cells changes from case to case depending on the degree of cell differentiation and maturation. In chronic myelocytic leukaemia there was no difference as compared to enzyme activity of myelocytes in bone marrow of control cases. Thus the bacteriolytic demonstration of lysozyme in blood smears may additionally contribute to distinction of different types of blastic leukaemias, and serum lysozyme also may allow more reliable insight into granulocytic and monocytic myelopoiesis than morphologic studies of blood or bone marrow smears can do, e.g. in agranulocytosis and pancytopenia.

[Hematologic toxicity of total body irradiation (author's transl)]. / Zur hämatologischen Toxizität der Ganzkörperbestrahlung.

Eleven patients with malignant lymphoma were treated with total body irradiation. This therapy was performed during 3 weeks with a midline dose of 70 to 100 rd. Two patients were treated two times after an internal of 3 months. The authors studied the hematologic side effects of this therapy. The irradiation caused a diminution of leucocytes of 73% of the initial value (range 16,7 to 98,4%), the neutrophilic granulocytes were reduced by 60% (24-95%), the thrombocytes were reduced by 57% (12-73%). The lowest values were seen during the fourth and sixth week of observation or one to three weeks after the end of therapy. In patients with hypoplastic anemia the number of reticulocytes was reduced to zero with a further fall of hematocrit and replacement therapy was necessary. The pool of circulating CFUc was reduced to zero in nine of twelve observations up to six weeks after therapy.

[Multiple myeloma and terminal acute myeloid leukaemia (author's transl)]. / Plasmozytom und finale unreifzellige Leukose

A patient with multiple myeloma died of an acute myeloid leukaemia 15 years after onset of the former. At time of diagnosis the 39 year-old-patient had bone marrow infiltration of maximally 32 plasma cells/100 white bone marrow cells, a paraprotein (IgG, light-chain type lambda), osteoporosis of late onset and occasional osteolysis. The long survival time, as well as the acute myeloid leukaemia, are probably due to the effective treatment, first with cyclophosphamide (198 g over four years), later melphalan (3000 mg over eight years).

Potentially toxic serum lidocaine concentrations following spray anesthesia for bronchoscopy.

Serum lidocaine concentrations were measured in a series of ten patients during and after topical lidocaine spray anesthesia used for diagnostic fiberoptic bronchoscopy. Mean total dose of lidocaine ranged from 480-720 mg. Peak serum lidocaine concentrations averaged 3.6 micrograms/ml (range: 1.9 to 7.4 micrograms/ml), and were attained shortly after the start of the procedure. Repeated topical administration of lidocaine spray therefore may lead to large cumulative doses and serum concentrations which are in the therapeutic or potentially toxic range.

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate.

The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions: in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min, P less than 0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.

Alprazolam kinetics in patients with renal insufficiency.

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.

[Aplastic anaemia and thymonal]. / Aplastische Anämie und Thymom

The combination of aplastic anaemia and thymona was observed in a 49-year old woman. Concomitant with severe normochromic anaemia and reticulocytopenia was a cell-rich bone marrow smear in which erythropoietic precursors were almost absent. Immunological phenomena could not be demonstrated. The erythropoietin level was maximally increased. Pathological anatomy typically revealed a predominantly spindle-cell thymonal with only minor capsular invasion.