Lack of efficacy of a short ex vivo incubation of human allogeneic donor marrow with recombinant human GM-CSF prior to its infusion into the recipient.

Ten patients with haematological malignancy receiving allogeneic transplants from donors other than HLA-identical siblings were prepared for marrow transplantation with antithymocyte globulin, cyclophosphamide 120 mg/kg and fractionated total body irradiation 12 Gy, and were given cyclosporin, methotrexate and prednisolone as prophylaxis against graft-versus-host disease post-transplant. The harvested T replete donor marrow was incubated with recombinant human (rh) GM-CSF 10 micrograms/ml (supersaturating concentration) for 1 h at 37 degrees C on a gently shaking rocker platform. After incubation the marrow was washed twice in 5% human serum albumin/normal saline and infused into the recipient. Before and after incubation, there was no significant difference in cell viability, the nucleated cell count, the CFU-GM content nor the proportion of cells in S phase of the cell cycle. Compared with a preceding cohort of 16 patients treated on the same protocol but in whom the marrow was not incubated with GM-CSF, there was no difference in the incidence of graft failure or rate of neutrophil recovery.

Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute inhibition of endopeptidase 24.11 in essential hypertension: SCH 34826 enhances atrial natriuretic peptide and natriuresis without lowering blood pressure.

The acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and efficacy of mometasone furoate cream in the treatment of steroid responsive dermatoses.

The safety and efficacy of once daily application of mometasone furoate cream 0.1% was determined by comparison with twice daily applications of betamethasone dipropionate cream 0.05% in a single blind, dual centre, randomized study in patients with a variety of steroid-responsive inflammatory dermatoses, the most common of which was psoriasis. Morning plasma cortisol levels revealed little adrenal suppression in either of the two study groups and there was no significant difference between the two groups. Routine laboratory investigations showed no trends in values outside the normal ranges that were of clinical significance. Less skin atrophy was seen in the group treated with mometasone furoate. In comparison to the betamethasone dipropionate treated group, those treated with mometasone furoate exhibited only slight evidence of skin atrophy, and this was not observed before four to twelve weeks of treatment. Eighteen percent of patients using mometasone reported adverse reactions but all were of limited duration and did not persist despite continued application of the drug. Nine percent of patients using betamethasone dipropionate reported adverse effects. Both drugs were found to be highly effective with no significant difference between the two groups at the termination of the treatment period. Of importance is the fact that whilst mometasone furoate is found to be a highly effective treatment for a variety of steroid-responsive dermatoses, this drug has only a limited potential for production of local and systemic side effects. Thus, a high margin of safety can be expected for patients using this drug.

Double-blind study of dilevalol and captopril, both in combination with hydrochlorothiazide, in patients with moderate to severe hypertension.

Sixty-one patients (41 men, 20 women) aged 29-73 years, with moderate to severe hypertension, were enrolled in a multicentre study to compare the efficacy, safety, and tolerability of dilevalol (D) and captopril (C). At the end of the baseline period, supine diastolic blood pressure (SuDBP) was 105-140 mm Hg on hydrochlorothiazide (HCTZ) 25 mg once daily and placebo t.i.d. Patients were randomly assigned to D + HCTZ (n = 29) or C + HCTZ (n = 32) and entered phase II titration of D (100-800 mg b.i.d.) or C (12.5 mg b.i.d. to 50 mg t.i.d.). If SuDBP was greater than 99 mm Hg, hydralazine was added (25 mg once daily to 50 mg b.i.d.). If SuDBP was less than or equal to 99 mm Hg, patients entered phase III, a 3-month maintenance period. Demographic profiles were not significantly different between the two groups. Baseline supine BP (mean +/- SEM) was similar in the two groups (D + HCTZ: 182 +/- 3/112 +/- 1; C + HCTZ: 179 +/- 4/113 +/- 1 mm Hg), as was baseline standing BP (D + HCTZ: 175 +/- 3/114 +/- 2; C +/- HCTZ: 173 +/- 4/113 +/- 1 mm Hg). At the end of phase II, there were no significant differences between treatments with respect to the changes in BP from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration.

A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses greater than or equal to 10 micrograms/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B12 levels increased during rhGM-CSF treatment. At doses of up to 15 micrograms/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels greater than or equal to 1 microgram/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.

Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy.

STUDY OBJECTIVE: To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). DESIGN: Single arm nonrandomized dose escalation study. PATIENTS: Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy. INTERVENTIONS: Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently. MEASUREMENTS AND MAIN RESULTS: All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient. CONCLUSIONS: Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.

Comparative study on the effects of recombinant alpha-2 interferon on immune function in patients with disseminated melanoma.

Fifteen patients with disseminated melanoma were treated by intravenous administration of recombinant alpha-2 interferon (rIFN-alpha 2) on 5 consecutive days every 2 weeks. Immunological studies on approximately 50% of the patients revealed no significant changes in lymphocyte numbers or T-cell subsets. Natural killer (NK) activity against the K562 target cell and a melanoma cell was increased in the first treatment cycle, but in subsequent treatment cycles it tended to decrease against the melanoma cell and to show either no change or moderate increases against the K562 target cell. Interleukin-2 (IL-2) production from mitogen-stimulated lymphocytes was decreased in most patients in each treatment cycle. This also applied to immunoglobulin production in vitro from pokeweed mitogen (PWM)-stimulated B and T cells. The latter was not due to the induction of radiation-sensitive suppressor T cells and may reflect effects on B cells or helper T cells. The repeated inhibition of IL-2 production with each cycle of treatment and the decrease in NK activity against the melanoma target cells after the first treatment cycle contrasted with the return to at or above pretreatment values of these tests when rIFN-alpha A was given intramuscularly on an alternate-day basis. It is suggested that these effects may be due to the relatively greater increase in endogenous cortisol production at the beginning of each treatment cycle in patients given rIFN-alpha 2 intravenously compared to that observed in patients treated with rIFN-alpha A on alternate days intramuscularly. Immunosuppression resulting from the increase in cortisol production may be one of the factors accounting for the low tumor response rate of patients in this study and may emphasize the possible importance of the schedule of rIFN-alpha administration for obtaining optimal antitumor responses.

Phase-II study of recombinant alpha 2-interferon in advanced malignant melanoma.

Fifteen patients with metastatic malignant melanoma, including 10 who had not previously received systemic therapy, were treated with recombinant alpha2-interferon (IFN-alpha 2) in a dose of 20 million IU/m2 by 30-min i.v. infusion daily for 5 days each 14 days. Evaluable metastatic sites included lung, subcutaneous tissue, liver, nodes, adrenals, and bone. Subjective toxicity was generally mild to moderate, with fever (38.2-40.2 degrees C), occasional rigors, fatigue, myalgia, headache, and nausea. Objective toxicity included transient neutropenia and elevation of hepatic enzymes, particularly gamma-glutamyl transpeptidase. In 1 of the 10 patients receiving more than one cycle, IFN dosage was reduced because of toxicity, but later reescalated. All patients were evaluated for response. No overall partial or complete responses were observed, but two site responses (lung and subcutaneous tissue) were seen. Median survival from start of IFN treatment was 19 weeks. High doses of IFN were reasonably well tolerated in this study, but the results suggest little activity against malignant melanoma.