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At least 19 recordsLinked to original sources
PubMed1990

A phase I trial with recombinant interferon gamma (Roussel UCLAF) in advanced cancer patients.

A total of 29 patients with advanced malignancy were treated with recombinant interferon gamma (rIFN gamma, specific activity = 2.10(7) units/mg, purity greater than 95%) given by intravenous bolus at doses escalating from 0.01 mg/m2 to 5 mg/m2 (2 x 10(5) - 10(8) IU/m2) in nine successive steps (at least 3 patients/step). Injections of rIFN gamma were repeated every 72 h for 15 days. Toxicity was evaluated according to the WHO scale. Fever and chills occurred in all patients treated without clear dose effect. Nausea and vomiting appeared at the fifth dose level and their frequency seemed to be dose-related. Cardiovascular side-effects (first-degree atrioventricular reversible block) were observed at the 2 mg/m2 and 5 mg/m2 levels (3 patients). Hematological toxicities were mild (2 grade 1 and 1 grade II cases of granulocytopenia). Minor biological modifications included a transitory rise in hepatic enzymes (12 patients), which correlated with the presence of liver metastasis. Hypocholesterolemia was observed in 18 patients. The appearance of antibodies against rIFN gamma was not detected. One partial clinical response was observed in a patient receiving 2 mg/m2. During rIFN gamma therapy this patient had the highest scores in this series for peripheral T lymphocytes with an activated phenotype (HLA DR+, TAC+) = 15% and for natural killer (NK) cells (NKH1, Leu19+) = 17%. rIFN gamma appears as a well-tolerated and promising therapeutic agent with toxicities and mode of action probably distinct from IFN alpha and beta.

Adult↗
PubMed1989

[Drug-induced renal insufficiency. Results of consensus meetings].

We report the conclusions of consensus meetings organized by the "Direction de la Pharmacovigilance" of Roussel Uclaf, and attended by University Hospital Nephrologists, members of the National Network of Pharmacovigilance and representatives of Roussel Uclaf Drug Monitoring Department, in order to define more accurately, as regards drug-induced renal failure, the criteria and the terminology proposed by the French method of causality assessment of adverse drug reactions.

Humans↗
PubMed1991

[Phase I trial of a recombinant human interleukin 2. Results in patients with disseminated solid tumors].

A phase I trial of Roussel-Uclaf recombinant human interleukin 2 (IL 2) was performed on 31 cancer bearing patients of the Institut Gustave-Roussy, Villejuif, and the Institut Curie, Paris. This study allowed to define a schedule for administration of IL 2 in continuous infusion over 5 day cycles. This schedule is manageable in patients without major visceral failure. It is reproducibly feasible in conventional medical oncology units, without specialized intensive care facilities. Toxicities, although numerous, are acceptable for IL 2 doses below 24,000,000 IU/m2/day. There is a close relationship between secondary effect severity and IL 2 doses received. Main toxicities were: fever with chills, fatigue and general discomfort in 23 patients, nauseas and vomiting in 12, diarrhea in 10 and cutaneous rashes with erythema and dermal vascularitis in 13. One peculiar feature of this study was the minimal occurrence of manifestation related to leaky capillary syndrome prominant in other studies. Oliguria, functional renal failure and edema were observed in only 4 patients with functionally unique kidney. Five patients had severe anemia, 2 grade III thrombocytopenia, 1 grade IV hepatic cytolysis, 4 severe confusion episodes and 2 hypothyroidism with anti-thyroid microsome auto-antibodies. All these toxicities were reversible after withdrawal of IL 2 treatment. During this phase I trial, 3 therapeutic objective responses were observed, all 3 occurring in patients with metastatic melanoma treated with IL 2 doses equal to, or above 16,000,00 IU/m2/d. Recombinant IL 2 Roussel-Uclaf thus can be administered through a simple, manageable and efficient regimen.

Adolescent↗
PubMed1992

Interleukin-2-induced increase of a monoclonal B-cell lymphocytosis. A novel in vivo interleukin-2 effect?

A 56-year-old man with refractory B-cell lymphocytic non-Hodgkin's lymphoma was treated in a Phase II study with interleukin-2 (IL-2) (Roussel-Uclaf, Romainville, France). The patient had involvement of multiple lymph nodes and medullary and peripheral blood (3.6 x 10(9) monoclonal CD19-positive [CD19+] B-lymphocytes/l). After a 5-day cycle of IL-2 treatment, an eightfold increase of the monoclonal CD19+ population was observed (27 x 10(9) monoclonal CD19+ cells). The lymphocytosis decreased dramatically during the second cycle (days 15 to 19) of IL-2 treatment, resulting in 6 x 10(9)/l peripheral lymphocytes, with 5.5 x 10(9) B-lymphocytes. As soon as day 20, peripheral B-cells again increased considerably, with 32 x 10(9) CD19+ cells/l at day 27. The CD19+ population remained monoclonal as assessed by kappa/lambda cell-surface phenotyping and kappa gene rearrangement evaluation. Kinetics of the monoclonal B-lymphocyte response to IL-2 paralleled the natural killer/lymphokine-activated killer and T-cell response, with a 4-day latency period, suggesting an indirect enhancing effect of IL-2. Before and during IL-2 treatment, peripheral B-lymphocytes never expressed detectable levels of the p55 IL-2 receptor. However, the p75 IL-2 receptor was expressed significantly in the IL-2-responsive monoclonal B-cell population. Tumor necrosis factor alpha, a known (in vitro) B-cell tumor growth factor, reached high serum levels during IL-2 treatment. Response evaluation at day 45 showed stability of the lymph node involvement and the marrow lymphocyte infiltrate. At day 45, peripheral B-cell lymphocytosis was 7.5 x 10(9)/l. To the knowledge of the authors, this is the first report of an in vivo IL-2-induced reversible increase of peripheral monoclonal B-cell lymphocytosis.

B-Lymphocytes↗
PubMed1993

Interleukin 2 treatment in acute myelogenous leukemia.

Significant clinical responses obtained with interleukin 2 (IL-2) in solid tumors such as renal cell cancer and malignant melanoma prompted the use of this immunomodulatory drug to verify its activity in hematological malignancies. Several preclinical experiments showed an activity of IL-2 against leukemic cell lines in cultures, particularly in acute myeloid leukemia (AML), while only episodically a proliferative stimulus of IL-2 on the growth of leukemic blasts has been observed. Based on these preclinical studies, in the past five years several phase I-II clinical trials have verified IL-2 activity in AML in advanced phase, both in patients with active disease and in patients in further complete remission (CR). Data obtained are difficult to evaluate due to the low number and the heterogeneity of patients treated, but encouraging results have been reported in patients with "limited" disease (bone marrow blastosis < 30%), showing an antileukemic activity of IL-2 alone. Different international phase III trials are ongoing in AML patients in I CR after autologous bone marrow transplantation (Roussel-Uclaf, Romainville, France) and in II CR after conventional chemotherapy (Roche SpA, Milan, Italy) to verify the efficacy of IL-2 in reducing the risk of relapse and prolonging disease-free survival.

Adolescent↗
PubMed1990

The effects of RU-38486 on cervical ripening. Clinical studies.

One hundred eighty pregnant patients, 17 to 39 years old (mean (+)/- SEM: 25.1 (+)/- 0.39), with an amenorrhea of 7 to 12 weeks (mean (+)/- SEM: 9.4 (+)/- 0.10), and requesting a therapeutic abortion, were selected according to general good health and gave their informed consent to the study. Mifepristone (RU-486; Roussel UCLAF, Paris, France) an antiprogestin steroid, was administered at random in doses of 0, 50, 100, 200, 400, or 600 mg. Clinical evaluations and measurements of cervical dilatation were done before the study and repeated at 24 hours after administration of Mifepristone and at 48 hours, at which time the aspiration was performed. Significant increases in cervical dilatation were observed at 48 hours with all doses of Mifepristone above 50 mg. The increases were significantly greater in patients with a gestational age greater than 10 weeks than in those less than 10 weeks' gestational age. Parity had no influence on cervical dilatation at 48 hours. Bleeding was observed significantly more often with 100 to 600 mg doses of Mifepristone than with 0 to 50 mg. No influence of gestational age or parity on bleeding could be detected. Abdominal cramps were reported more frequently with 200, 400, and 600 mg of Mifepristone at 48 hours and their occurrence appeared to parallel cervical dilatation.

Abortion, Induced↗
PubMed1987

Evaluation of RU-27987 as a ligand to determine the progesterone receptor.

RU-27987, a synthetic progestin, which was recently developed by Roussel Uclaf, Paris, was tested for its validity as a ligand to determine the progesterone receptor in breast cancer. The results were compared to those obtained with R-5020 and ORG-2058, two ligands that are already in use worldwide. The intra- and interassay variation of receptor determination was similar for all 3 ligands. Receptor levels were analyzed with each of the 3 progestins in control cytosols and in 26 mammary carcinoma samples. A good correlation between receptor levels was found although the values of ORG-2058 were somewhat lower, but not significantly. This resulted in a lower proportion of receptor positive samples for ORG-2058 (11/26) compared to R-5020 (13/26) and RU-27987 (14/26). The affinity to the progesterone and to the glucocorticoid receptor, as well as the precision of the Scatchard plot analysis were comparable for the 3 ligands tested. Intra- and interassay variation of receptor determination were also similar. We therefore conclude, that RU-27987 is a suitable ligand to determine progesterone receptor in mammary carcinoma.

Breast Neoplasms↗
PubMed1988

Induced cervical ripening with Mifepristone in first trimester abortion. A double-blind randomized biomechanical study.

Mifepristone (RU 486; Roussel-Uclaf, Paris, France) is an antiprogesterone used for termination of very early pregnancy. The ripening effect of Mifepristone on the human pregnant cervix was studied in 42 healthy women from 7 to 11 weeks gestation. The women were randomly allocated to oral treatment of either 100 mg Mifepristone or placebo for 24 and 12 hours before vacuum aspiration. An objective method has been designed to measure the force necessary to step-wise dilate the cervix from 4 to 11 mm. Significant (p less than 0.05) changes in the stiffness of the cervix were demonstrated in patients treated with Mifepristone, reflecting ripeness. The treatment was simple and had no side effects.

Abortion, Induced↗
PubMed1989

3H-ZK 98,734, a new 11 beta-aryl substituted antigestagen: binding characteristics to receptor and serum proteins.

Recently, in the laboratories of Schering in Germany a competitive progesterone antagonist, ZK 98,734, was synthetized, which is characterized by a similar antigestagenic activity as RU 38,486, synthezised by Roussel-Uclaf in France, as assessed by inhibition of nidation tests in rats and guinea pigs. However, this compound has a substantially lower antiglucocorticoid activity measured in cell culture systems than RU 38,486. The purpose of this study was to present a comparison of biochemical and physical properties of the complexes formed by the human uterine progesterone receptor with 3H-ZK 98,734 on one hand and with other well-established progestins on the other hand. ZK 98,734 competed in the same order of magnitude as progesterone or RU 38,486 for the 3H-R5020 binding site of progestin receptor, whereas R5020, Org 2058 or progesterone were unable to compete against 3H-ZK 98,734. This apparent contradiction could be explained by means of FPLC-chromatography and sucrose density centrifugation technique. FPLC-chromatography with an anion exchange column (Mono Q, Pharmacia, Uppsala, Sweden) showed that 3H-ZK 98,734 forms at least two stable complexes with uterine cytosol, on one hand with serum albumin, which presents almost 90% of bound radioactivity, and on the other hand with the two native progestin receptor forms, corresponding to 4S and 8S receptor forms in sucrose density gradient analysis. Competition experiments in liver cytosol of adrenalectomized rats with increasing concentrations of unlabeled ligands other than dexamethasone showed that ZK 98,734, RU 38,486 and cortisol displaced 3H-dexamethasone efficiently from the binding sites in the cytosol. Furthermore, results concerning the specificity of 3H-cortisol binding to serum proteins in diluted pregnant serum demonstrated that ZK 98,734 did not compete with 3H-cortisol for serum binding.

Animals↗
PubMed1990

Mifepristone (RU 486) for cervical priming prior to surgically induced abortion in the late first trimester.

Mifepristone (RU 486; Roussell-Uclaf, Paris, France) is an antiprogesterone agent, which has been used successfully in combination with prostaglandin for early pregnancy medical abortion. Forty primigravidae were studied from 10-13 weeks of gestation. Women were randomly allocated to receive either placebo or a 600 mg single oral dose of Mifepristone 48 hours prior to vacuum aspiration under general anaesthesia. An objective mechanical method was used to assess the dilatation of the cervix at surgery. In 35% of the treated patients, there was no need for further dilatation prior to evacuation of the uterus. All patients in the placebo group required further dilatation (p less than 0.001). In those patients receiving Mifepristone who did require further dilatation, the initial dilatation of the cervix was significantly greater (p less than 0.01) and significantly less force was required to dilate the cervix to 9 mm (p less than 0.001). Perioperative blood loss was reduced. There were no serious complications or side effects. Mifepristone for cervical priming is safe and effective and has advantages over prostaglandins and hydrophilic cervical dilators.

Abortion, Induced↗
PubMed1984

An approach to the mechanism of the potent antiglucocorticoid: 17 beta-hydroxy-11 beta-4-dimethylaminophenyl-17 alpha-propynyl-estra-4,9-dien-3-one.

The effects of a new synthetic steroid, 17 beta-hydroxy-11 beta-4-dimethyl-aminophenyl-17 alpha-propynyl-estra-4,9-dien-3-one, classified under reference R38486 in the Roussel-Uclaf nomenclature [1], were investigated in two established rat hepatoma cell lines in order to gain information on the mechanism of action. The induction of tyrosine aminotransferase (TAT) and alanine aminotransferase (AAT) was totally abolished when R38486 was added with dexamethasone either on a 1-1 basis or on a 10-fold excess depending on the differentiation state of the cell. Binding studies showed a high affinity for the glucocorticoid receptor; however our "whole cell" study with [3H] R38486 indicates that only a low amount of antagonist-receptor complexes was translocated into the nucleus. Nuclear fractionation experiments showed that R38486, like the other antagonists studied, was located in the chromatin fraction where it may exert some definite role. Our observations based on whole cell experiments using physiological doses of glucocorticoid analogs indicate that the binding of activated antiglucocorticoid-receptor complexes to nuclear acceptor sites represents a physiologically significant process. Moreover the differences in the nuclear binding of antagonist-receptor- as compared to agonist-receptor-complexes may set off the machinery of antagonistic action.

Animals↗
PubMed1985

The antiglucocorticoid RU486 inhibits the ethanol-induced increase of tryptophan oxygenase.

The effect of the glucocorticoid-antagonist RU486 (Roussel-Uclaf, France) on the increased activity of hepatic tryptophan oxygenase (TO) after administration of corticosterone and ethanol in rats was studied. RU486 (40 mg/kg per os) inhibited completely the effect of corticosterone (5-15 mg/kg injected intraperitoneally) on TO. Ethanol (4 g/kg) given intraperitoneally is followed by peak corticosterone concentrations comparable to those seen after the administration of 5-10 mg exogenous corticosterone, and increased the TO activity 3-fold 4 h after the injection. RU486 inhibited completely the ethanol-induced increase of TO, indicating that this increase is mediated by corticosterone.

Animals↗
PubMed1988

How the study of the biological activities of antiandrogens can be oriented towards the clinic.

Antiandrogens can be used in various androgen-dependent diseases. Depending upon the therapeutic indication, they can be administered systemically or topically. Systemic treatment with an antiandrogen will inhibit androgen action not only in the desired target site but also in all other target tissues; thus, it will block the androgen-dependent feedback regulating the secretion (hypothalamo-pituitary-testis axis) or the action (protein factors) of androgens. In contrast, topical treatment (acting through cutaneous receptors or local metabolism) should not produce systemic side effects especially in man. Pharmacological assays which can select antiandrogens irrespective of the mechanism measure changes in the final androgenic response, but they consume a great deal of time and test compound and bear little relation to therapeutic activity. Therefore, the biological strategy that we report here and which, at Roussel-Uclaf, has led to the selection of a systemic and a topical antiandrogen (RU 23908 and RU 38882) has consisted in successively performing: (1) in vitro assays which measure an effect at a specific level in the mechanism of antiandrogen action, e.g. interaction with the androgen receptor. Assessing interactions with other classes of steroid hormone receptor can be used to predict possible hormonal side-effects, (2) in vitro determinations of agonist or antagonist activity, e.g. in pituitary cells (LH response to LHRH) or mammary tumor cells (induction of androgen-dependent proteins), (3) in vivo antiandrogen assays after a single treatment (induction of mouse kidney proteins, rat prostatic binding protein) or after repeated treatment (inhibition of the growth of rat accessory glands or of hamster sebaceous glands), to determine the active dose of the compound and possibly the absence of systemic effects by the topical route, (4) assays in animal models designed to mimic a therapeutic context e.g. for prostate cancer: inhibition of the "flare-up" effect of LHRH-A or of the trophic effect of perfused adrenal androgens on rat prostate, antitumoral activity in experimental cancer models. For hyperseborrhoea and acne: histological and stereological analysis of rat skin biopsies to measure the volume density of the smooth endoplasmic reticulum vesicles of the differentiating cells of the sebaceous gland.

Androgen Antagonists↗
PubMed1989

The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death.

The antiprogesterones Onapristone, ZK 112.993 (Schering AG), and Mifepristone (Roussel-Uclaf) proved to possess progesterone receptor-mediated antiproliferative effects in experimental mammary carcinomas. In this study, the potency and mechanism of the antitumor action of Onapristone and ZK 112.993 is characterized by ovariectomized, progestagen and/or estradiol substituted mice bearing hormone-dependent MXT(+) mammary tumours. Medroxyprogesterone acetate (MPA, 0.8 mg/mouse, 3 times weekly, s.c.) could only induce a poor stimulation of tumour growth (% T/C = 40; intact control % T/C = 100), which was only marginally inhibited (% T/C = 21) by Onapristone (0.2 mg/mouse, 6 times weekly, s.c.) during a 6-week therapy. Therefore, the antitumor mechanism of antiprogesterones cannot preferably depend on a classical progesterone antagonism. In contrary, the pronounced stimulation of tumor growth (% T/C = 152) by estradiol benzoate (EB, 0.33 microgram/mouse, 3 times weekly, s.c.) was completely inhibited (% T/C = 7) by the antiprogesterones. An even more stimulated tumour growth was achieved by a combination of EB and MPA (% T/C = 365 using 0.17 mg; % T/C = 225 using 0.8 mg MPA). Onapristone dramatically blocked tumor growth (% T/C = 7) at the lower dose of MPA; no inhibition (% T/C = 203), however, was detected at the higher dose of MPA. These data and a morphological analysis indicate that the potent antitumor activity of the progesterone antagonists depends on the binding to a number of available progesterone receptors high enough to trigger an antiproliferative effect via the induction of terminal differentiation associated with terminal cell death.

Animals↗