Showing papers by "Roussel Uclaf published in 1988"

Evidence that monoclonal antibody production kinetics is related to the integral of the viable cells curve in batch systems

Abstract: Monoclonal antibody production kinetics in batch systems is linearly related to the integral of the viable cells curve. This favors the secretion theory over that of release by dead cells. Regression of the production curve over the integral of the viable cells curve in different media can also give information on the nutritional requirements of the cells for growth and production.

4-Hydroxy-3-quinolinecarboxamides with antiarthritic and analgesic activities.

Abstract: A series of 4-hydroxy-3-quinolinecarboxamides has been synthesized and evaluated by the oral route as antiinflammatory agents in carrageenin-induced foot edema and adjuvant-induced arthritis and as analgesic agents in the acetic acid induced writhing test. Among the most active molecules, some have shown both analgesic and acute antiinflammatory activities. Others, such as compounds 24, 37, and 52, were only powerful peripherally acting analgesics. Compound 52, being active at 1 mg/kg (ED50), is the most potent compound in the series. Some analogues, substituted in the 2-position by an alcohol, ester, or amine function, displayed potent antiarthritic activity in the same range as that of piroxicam and were also active in acute tests of inflammation and nociception. They inhibited the activity of both cyclooxygenase and 5-lipoxygenase at micromolar concentrations. Compound 102 (RU 43526) showed potent antiarthritic activity (adjuvant-induced arthritis, ED50 = 0.7 mg/kg, po) and gastrointestinal tolerance (ED100 greater than 250 mg/kg, po) and thus it is presently undergoing an extensive pharmacological evaluation.

Binding of steroids to the progestin and glucocorticoid receptors analyzed by correspondence analysis.

Abstract: The relative binding affinities of over 30 steroids have been measured for the cytosol glucocorticoid receptor (GR) of thymus, liver, and hepatoma tissue culture cells and for progestin, androgen, and mineralocorticoid receptors. The data have been analyzed by correspondence analysis to reveal the singularities among the receptors of different hormonal classes, the similarities in GR of different origins, and the different specificities of the ligands. Additional data on new steroids have been injected into the system as well as results on a further parameter, namely the induction of tyrosine aminotransferase (TAT) activity, to illustrate the power and flexibility of the methodology. The analysis has confirmed previous correlations between GR binding and TAT response but also highlighted the antiglucocorticoid activity of progestins. This method should prove to be a substantial aid to the interpretation of increasingly complex data, in particular with regard to the action of existing and newly synthesized steroids on glucocorticoid systems of differential sensitivity.

Novel 19-nor-steroids

Abstract: Novel 19-nor-steroids of the formula ##STR1## wherein the A ring is either ##STR2## Re is selected from the group consisting of hydrogen, acyl and optionally substituted alkyl of 1 to 6 carbon atoms, R is methyl or ethyl, R1 is selected from the group consisting of hydroxyl, protected hydroxyl, acyloxy and alkoxy, R2 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl and alkynyl of 2 to 8 carbon atoms, acyl, aralkyl of 7 to 15 carbon atoms, the substituents other than hydrogen being optionally substituted or R1 and R2 together form a group selected from the group consisting of ##STR3## Ar is an optionally substituted 5- or 6-membered aryl and their salts with non-toxic, pharmaceutically acceptable bases and acids having antiproliferative, anti-estrogenic and/or estrogenic properties.

Methodological proposal in behavioural teratogenicity testing: Assessment of propoxyphene, chlorpromazine, and vitamin A as positive controls

Abstract: Pregnant Sprague-Dawley rats received either 80 mg/kg d-propoxyphene HCl or 20 mg/kg chlorpromazine HCl or 80,000 and 160,000 IU/kg vitamin A palmitate daily between the 6th and 20th days of gestation. Vehicle control groups were similarly treated with saline or corn oil and considered as negative controls. Offspring were examined for physical landmarks, neuromotor development, and behaviour using righting reflex, swimming, negative geotaxis, open field, rotarod, water maze, and nocturnal activity. This test battery included biochemical measurements. No reduction in parental weight and physical offspring development was observed. All these treatments produced long-term changes in more than one test. Vitamin A palmitate (160,000 IU/kg) was judged as the best positive control with this test battery for future investigation of the behavioural teratology of drugs.

Activation and infection of B cells by Epstein-Barr virus. Role of calcium mobilization and of protein kinase C translocation.

Abstract: Both the activation and the transformation of human B cells by EBV were inhibited by either the Ca2+ channel blocking agent verapamil or the combination of theophylline and dibutyryl cAMP: the day 4 and day 20 peaks of [3H]TdR incorporation were abolished; the EBNA marker was not expressed by day 10; lymphoblastoid cell lines did not arise. Short term incubation of B cells with EBV or verapamil showed that the effect of verapamil was reversible and took place early in the interaction between EBV and B cells. The effect of EBV on the early metabolic events of B cell response was thus examined in the presence and in the absence of the drugs. Compared to anti-mu stimulation, supernatant of the transforming B95-8 strain as well as that of the non-transforming P3HR1 strain induced a drug sensitive increase of the free cytosolic Ca2+ concentration. This increase was associated with a protein kinase C translocation from the cytosol to a membrane bound compartment. Moreover, B95-8 supernatant induced phosphatidyl inositol metabolism by human B cells but at least four times less than that induced by anti-mu antibody. These metabolic events induced by EBV were significantly inhibited by anti-CD21 antibodies whereas anti-mu induced metabolic events were not. The infection of EBV negative Ramos cell line was prevented by verapamil or by theophylline + dibutyryl cAMP. Verapamil did not modify the density of EBV receptors but negatively interfered with the penetration of the virus into B cells. Thus B cell activation through the EBV receptor and virus penetration share a common metabolic pathway which is also used for transduction of the signal delivered through the membrane Ig.

No effect of roxithromycin on pharmacokinetic or pharmacodynamic properties of warfarin and its enantiomers.

Abstract: The macrolide antibiotics are metabolized by cytochrome P-450 enzymes in the liver and interactions with similarly metabolized compounds have been described. Simultaneous treatment with erythromycin and warfarin is known to decrease warfarin clearance and prolong prothrombin time. Roxithromycin (RU 28965), a new erythromycin derivative with improved pharmacokinetic properties, might then, because of structure similarity, be expected to interact with warfarin. In 21 healthy volunteers, the effect of orally administered roxithromycin (150 mg b.i.d.) on warfarin steady-state kinetics, and the effects of warfarin on roxithromycin kinetics, were investigated in a double-blind, randomized study versus placebo. Since the warfarin enantiomers, R- and S-warfarin have both different potency and different metabolism, the ratio between the enantiomers with and without roxithromycin, was also determined. In this study, mean AUC for warfarin increased slightly from day 14 of warfarin treatment to day 28, but no difference was found between the roxithromycin group and the placebo group, and no change appeared in the ratio between the warfarin enantiomers. A moderate increase in dosage was needed to maintain hypocoagulability during warfarin medication, but there was no difference between the roxithromycin group and the placebo groups, respectively. In addition, roxithromycin kinetics appeared to be unaffected by warfarin treatment.

Novel 17 beta -hydroxy-19-nor-steroids

Abstract: Novel 19-nor steroids of the formula I wherein R' is selected from the group consisting of propyl, propenyl, iodoethenyl, iodoethynyl or -C 3BOND C-CH2-Hal1, Hal1 is selected from the group consisting of fluorine, chlorine and bromine and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antiglucocorticoid and antiprogestomimetic activity.

Acute effects of amitriptyline on human performance and interactions with diazepam.

Abstract: The effects of psychomotor performance and attention of amitriptyline 75 mg administered without and with diazepam 10 mg have been investigated in 12 healthy subjects. The effects of the compounds were evaluated by objective tests (measurement of body sway, critical flicker fusion, visual reaction time, tachistoscopy, short term visual memory, tapping test, arithmetical calculation and Clement's code) and subjective measurements (visual analogue scales and side effects questionnaire). Measurements were taken before treatment and after 1, 3, 6, 8 and 24 h. Placebo did not affect either the objective or the subjective measurements. Diazepam caused a reduction in attention and performance after 1 h which had disappeared at 3 h. Amitriptyline caused a marked reduction in attention and performance, reaching a peak 3 hours after drug administration and persisting until 8 h. the deterioration in vigilance induced by amitriptyline was potentiated by concomitant diazepam.

Steroids with a 3,4 or 6 ring members spiro ring at position 17, their preparation, intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing them

Abstract: Products of formula (I): … … in which:… R1 = optionally substituted carbocyclic or heterocyclic aryl or aralkyl radical,… R2 = in position alpha or beta = hydrocarbon radical of 1 to 18 carbon atoms,… X = -(CH2)n- with n = 1, 2 or 4 or X = -CH=CH-CH2-CH2-… A, B and C = especially: … … process and intermediates for their preparation, their application as medications and pharmaceutical compositions containing them.

17-Aryl steroids, their preparation and intermediates for their preparation, their use as medicines and pharmaceutical compositions containing them

Abstract: Products of the formula … … in which… R1 = C1-18 organic radical… R2 = CH3 or C2H5… A and B … … Re = H, C1-6 Alk or acyl … … R3 or R4 denote: one optionally protected or acylated OH or alkoxy and the other optionally substituted aryl,… R5: optionally substituted aryl,… process and intermediates for their preparation, their application as medications and the pharmaceutical compositions containing them

Controlled release means

Abstract: A controlled release means comprisng a core of at least one water-soluble ingredient of which at least one ingredient is to be released in a controlled manner, said core being surrounded by a semi-permeable membrane coating containing dispersed water-soluble pore-forming particles in sufficient amount to give rise to dissolution upon exposure to an aqueous environment to form only one or two pores extending through the coating to provide communication between the core and the exterior of the coating and a method of making the same.

Antiandrogens in combination with LH-RH agonists in prostate cancer.

Abstract: The rationale of the combination of a nonsteroid antiandrogen with an LH-RH analogue (LH-RH-A) in the treatment of prostate cancer is discussed Whereas the LH-RH-A depresses testosterone (T) levels via an action on the hypothalamus-pituitary-gonad axis, the antiandrogen counters the effect of any residual T, from the testes or adrenals, on the target organ, the prostate Although bilateral orchiectomy and administration of estrogen or LH-RH-A give equivalent low T levels over long-term treatment, the manner and rate at which T suppression is achieved vary and each treatment presents characteristic disadvantages Orchiectomy is irreversible, and it is known that approximately 20% of patients will not benefit from such endocrine manipulation, estrogen use is associated with cardiovascular disease, and LH-RH analogues produce an early surge in T None of these treatments has any significant effect on adrenal androgen levels, which may contribute toward the progression of disease Nonsteroid antiandrogens such as anandron and flutamide inhibit the uptake of androgen by the prostate by an action that probably involves the androgen receptor They do not possess the progestational and glucocorticoid component of steroid antiandrogens or their pituitary inhibitory activity but do exert some inhibition of the 17 alpha-hydroxylase and 17,20-lyase enzyme systems Unlike steroids, the nonsteroid antiandrogens potentiate the activity of LH-RH-A at the central level in the rat The inhibitory action of the combined treatment of "anandron + buserelin" on the prostate is greater than that of each compound alone Clinical pharmacology studies have demonstrated that both steroid and nonsteroid antiandrogens can help to control the effect of increased T levels (disease flare) that occur on initiating LH-RH-A administration Prostatic acid phosphatase (PAP) levels decrease immediately in spite of the increase in T The decrease appears faster when nonsteroid antiandrogens are used Nonsteroid antiandrogens sensitize the pituitary to stimulation by LH-RH in eugonadal volunteers The results of randomized clinical studies with the combination of "nonsteroid antiandrogen + LH-RH-A" have established a definite trend toward greater efficacy of the combined treatment over monotherapy Further data are needed to confirm this trend In particular, further dose-ranging studies are warranted since the need for LH-RH-A doses that reduce T down to castration levels may not be justified in the presence of a potent antiandrogen(ABSTRACT TRUNCATED AT 400 WORDS)

Novel 17-hetero substituted steroids

Abstract: Steroids with a 17-spiro substituent of 3,4 or 6 ring members of the formula ##STR1## wherein R 1 is selected from the group consisting of carbocyclic aryl, heterocyclic aryl and aralkyl, R 2 is a hydrocarbon of 1 to 18 carbon atoms in the α-or β-position, the wavy line of the spiro ether indicates the oxygen is α-or β-, X is selected from the group consisting of --CH═CH--CH 2 --CH 2 -- and --(CH 2 ) n --, n is 1, 2 or 4, the A and B rings have a structure selected from the group consisting of ##STR2## R' and R" are individually hydrogen or alkyl of 1 to 4 carbon atoms, R e is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms and acyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antiprogestomimetic activity.

Cephalosporins having in position 3 a substituted vinyl radical, their process for preparation, their application as medicaments, compositions containing them and intermediates

Abstract: Products of formula (I): … … syn isomer… in which:… R = H, alkyl, alkenyl, alkynyl or cycloalkyl, optionally substituted, … … A = H, alkali metal, alkaline-earth metal, magnesium, organic base or CO2A = CO2 and their salts, process for their preparation, their application as medications, compositions containing them and the new intermediates obtained.

Microbiological preparation of 9-alpha-hydroxy-17-keto steroids

Abstract: 9α-hydroxy-17-keto steroids are prepared by fermenting steroids having a C-17-side chain of 5-10 carbon atoms inclusive, with the novel Mycobacterium species CBS 482.86. Starting from various substrates containing a 5-10 C carbon chain on C-17, 9α-hydroxyandrost-4-ene-3,17-dione, 7α,9α,12α-trihydroxyandrost-4-ene-3,17-dione or 9α-hydroxyandrost-4,11-diene-3,17-dione is obtained in high yield. The resulting compounds are useful intermediates in the synthesis of therapeutically important steroids, particularly corticosteroids.