Showing papers by "Novartis published in 1985"

Cloning and expression of cDNA for rat heme oxygenase.

Abstract: Two cDNA clones for rat heme oxygenase have been isolated from a rat spleen cDNA library in lambda gt11 by immunological screening using a specific polyclonal antibody. One of these clones has an insert of 1530 nucleotides that contains the entire protein-coding region. To confirm that the isolated cDNA encodes heme oxygenase, we transfected monkey kidney cells (COS-7) with the cDNA carried in a simian virus 40 vector. The heme oxygenase was highly expressed in endoplasmic reticulum of transfected cells. The nucleotide sequence of the cloned cDNA was determined and the primary structure of heme oxygenase was deduced. Heme oxygenase is composed of 289 amino acids and has one hydrophobic segment at its carboxyl terminus, which is probably important for the insertion of heme oxygenase into endoplasmic reticulum. The cloned cDNA was used to analyze the induction of heme oxygenase in rat liver by treatment with CoCl2 or with hemin. RNA blot analysis showed that both CoCl2 and hemin increased the amount of hybridizable mRNA, suggesting that these substances may act at the transcriptional level to increase the amount of heme oxygenase.

Primary structure of the precursor to the three major surface antigens of Plasmodium falciparum merozoites.

Abstract: Recently, a class of protein antigens of high relative molecular mass (Mt) which can induce protective immunity against blood-stage malaria has been identified. In Plasmodium falciparum the protein has a Mr of approximately 195,000 (P195). It is the precursor of three proteins of Mr 83,000 (83K), 42K and 19K which are the major surface antigens of merozoites; thus it may also be useful for immunization against P. falciparum. Three studies describing the isolation of single short complementary DNA clones for part of the P195 gene sequence have been reported. Here we describe the complete structure of the P195 gene determined from further DNA clones, its organization within genomic DNA and the location of the specific processing fragments within the primary amino-acid sequence.

Cassette of Eight Exons Shared by Genes for LDL Receptor and EGF Precursor

Abstract: The amino acid sequences of the human low-density lipoprotein (LDL) receptor and the human precursor for epidermal growth factor (EGF) show 33 percent identity over a stretch of 400 residues. This region of homologous is encoded by eight contiguous exons in each respective gene. Of the nine introns that separate these exons, five are located in identical positions in the two protein sequences. This finding suggests that the homologous region may have resulted from a duplication of an ancestral gene and that the two genes evolved further by recruitment of exons from other genes, which provided the specific functional domains of the LDL receptor and the EGF precursor.

Evaluation of monoclonal antibodies for the development of breast cancer immunotoxins

Abstract: Eighty-five antibodies recognizing breast cancer-selective antigens were conjugated to ricin toxin A-chain using a disulfide linkage. The cytotoxicities of the resulting immunotoxins were determined on breast cancer cells and normal human fibroblasts. Twenty-four antibodies formed immunotoxins that were toxic to at least one breast cancer cell line at concentrations of 10 nM or less but were nontoxic to human fibroblast lines used as negative controls. Some of the breast tumor-selective immunotoxins were as toxic as a conjugate between monoclonal anti-transferrin receptor and ricin toxin A-chain (50% inhibition of cellular protein synthesis at approximately 0.1 nM). Another set of four immunotoxins were indiscriminately toxic to human breast tumor cell lines, two human fibroblast cell lines, and a human lymphoblastoid line. Several of the antibodies the toxin conjugates of which specifically killed breast cancer cell lines may be useful in cancer therapy, since they show a wide range of binding to individual breast tumors and cell lines and a limited range of binding to normal tissue types.

Modification of the carbohydrate in ricin with metaperiodate — cyanoborohydride mixtures: Effects on toxicity and in vivo distribution

Abstract: Attempts to target antibody-ricin conjugates (immunotoxins) to designated cell types in vivo may be thwarted by their rapid clearance by hepatic reticuloendothelial cells which have receptors that recognise oligosaccharide side chains on the toxin. The B-chain of ricin contains high mannose type oligosaccharides and the A-chain contains a complex unit (GlcNAc)2-Fuc-Xyl-(Man)4–6, all of which potentially could be recognised by the reticuloendothelial system. Treatment of ricin with a mixture of sodium metaperiodate and sodium cyanoborohydride at pH 3.5 resulted in oxidative cleavage of the carbohydrates and reduction of the aldehyde groups thus formed to primary alcohols. By conducting the modification procedure at acidic pH, both the possibility of Schiff's base formation between the aldehyde groups and amino groups in the protein and the possibility of non-specific oxidation of amino acids were minimised. The extent of the carbohydrate modification depended on the duration of treatment, resulting maximally in the destruction of 13 of the 18 mannose residues and of all xylose and fucose. The toxicity of the modified toxin to cells in culture declined by up to 90% as the carbohydrate was destroyed. This was not due to a reduced ability of the B-chain to bind to cells or of the A-chain to inactivate ribosomes. In contrast to the in vitro results, the toxicity of the modified toxin to mice and rats was elevated by up to fourfold. The modification greatly reduced the clearance of the toxin by non-parenchymal cells in the liver and prevented the damage to hepatic Kupffer and sinusoidal cells and to the red pulp of the spleen that is inflicted by the native toxin. The elevated toxicity to animals appears to be because the modified toxin evades the reticuloendothelial system and persists in the bloodstream for longer periods, thus resulting in lethal damage to vital tissues in the animal at lower dosage. The results suggest that immunotoxins prepared from modified ricin would not be readily cleared by the reticuloendothelial system and so be more effective at killing their target cells.

Multicompartmentalized transdermal patches

Abstract: A dermal or transdermal patch comprising (1) a backing layer which is non-permeable with respect to a drug formulation to be contained within the patch, (2) a membranous layer, which is permeable to the drug, having a first surface partially in contact with said backing layer so as to define multiple compartments, (3) at least one drug or drug formulation contained within said compartments, (4) an adhesive layer on a second surface of said membranes layer, and (5) a peelable protective cover layer on said adhesive layer.

Spontaneous preparation of small unilamellar liposomes

Abstract: The present invention relates to a novel advantageous process for the preparation of unilamellar liposomes in aqueous phase by converting a suitable lipid component, e.g. phosphatidic acid, into the ionic form by subjecting the lipid dispersion to a change in pH value and subsequently neutralizing it. Formation of the unilamellar liposomes is spontaneous, i.e. it takes place without additional external supply of energy. The liposomes obtainable by the process of this invention can be used therapeutically as carriers for drugs of the most widely different kind.

Antigen Engineering in Yeast: Synthesis and Assembly of Hybrid Hepatitis B Surface Antigen-Herpes Simplex 1 gD Particles

Abstract: A new approach for antigen presentation and polyvalent vaccines is tested. The idea is to recombine the gene of a second immunogen with that of hepatitis B surface antigen so that the second immunogen is assembled into, and presented on the surface of the HBsAg particle. We describe here the synthesis and assembly in yeast of a model hybrid particle containing both, hepatitis B virus and herpes simplex virus surface antigens.

Transformation of hereditary material of plants

Abstract: A novel process for the direct transfer of foreign genes to plant genomes is described. The novel process comprises placing a gene under the control of plant expression signals and transferring it, by contact with protoplasts without the aid of natural systems for infecting plants, direct to plant cells from which genetically transformed plants can subsequently be derived.

Rheumatic fever‐associated B cell alloantigens as identified by monoclonal antibodies

Abstract: Mice immunized with B lymphocytes obtained from patients who had had well-documented rheumatic fever in the past yielded 2 monoclonal antibodies, termed 83S19.23 and 256S10, which identified certain alloantigens present on the B cells of these patients. The frequency of the B cell marker detected by clone 83S19.23 in rheumatic fever patients was found to be 59%, 77%, and 74% in India, New Mexico, and New York, respectively. Monoclonal antibody 256S10 identified 75% of those rheumatic fever patients who were nonreactive to clone 83S19.23. Thus, the 2 antibodies identify approximately 92% of all rheumatic fever patients and suggest the presence of a diallelic genetic marker for susceptibility to rheumatic fever.

Characterization of the polypeptide composition of human factor VIII:C and the nucleotide sequence and expression of the human kidney cDNA.

Abstract: Human coagulation factor VIII:C has been purified approximately 5000-fold from commercial preparations with an average activity yield of 35%. Proteins of 92 kD and 77–80 kD enriched during purification are precipitated by a human serum polyclonal antibody which inhibits factor VIII:C activity. Evidence suggests that these polypeptides are linked by a calcium ion bridge. Partial amino acid sequence information from these proteins has been obtained from the intact polypeptides and from products of digestion with thrombin, endoproteinase lysC, or trypsin after citraconylation. An oligonucleotide probe designed from one of the amino acid sequences was used to isolate a partial genomic clone from a human 4X chromosome library in bacteriophage λ. The genomic segment was used to isolate two cDNA molecules encompassing the entire human kidney factor VIII:C mRNA. Biologically active factor VIII:C has been produced in a mammalian cell line utilizing a complete cDNA construction.

Thermally transferable layers of radiation sensitive epoxy resins used to prepare protective coatings and relief images

Abstract: A process for the production of a protective layer or a relief image on a substrate, wherein a radiation-sensitive layer, consisting of a solid film-forming epoxy resin containing a photoinitiator, which can be activated by radiation, for the polyaddition reaction, is transferred from a support to a substrate, then exposed directly or under a photomask and hardened by the action of heat, after which, if appropriate, the unexposed parts are developed with a solvent. The process is suitable, for example, for the production of printed circuits, solder resist masks and offset printing plates.

Substituted propane-phosphonous acid compounds

Abstract: Compounds of the formula I ##STR1## wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms, and wherein one of the groups R1, R2 and R3 represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another one of R1, R2 and R3 is hydrogen or, in the case of R1 and R2, is hydroxy, and the remaining one of R1, R2 and R3 is hydrogen, or wherein R denotes methyl, R1 denotes hydrogen or hydroxy, R2 denotes an aromatic radical and R3 represents hydrogen, and their salts have GABAB -antagonistic properties and can be used as GABAB -antagonists. They are obtained when in a compound of formula II ##STR2## in which R, R1, R2 and R3 have their previous significances, Z represents --NH2 and R4 denotes a hydroxy-protective group R5 or, when R1 and R3 denote hydrogen and R2 denotes hydrogen or alkyl, denotes an alkali metal or ammonium ion R6, or Z represents a protected or latent amino group Zo and R4 denotes hydrogen or a hydroxy-protective group R5, any group R5 or R6 is replaced by hydrogen, and/or any group Zo is converted into --NH2.

Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use

Abstract: An active agent containing controlled release diffusion device comprising a swellable hydrogel matrix in the non-swollen state, interpenetrated with an active agent solute having a stable concentration distribution increasing in a gradient normal to the surface of the device and between the surface and the core thereof, said gradient being in the form of a substantially continuous, inflection point containing, sigmoidal curve, such that the device, when placed in an aqueous hydrogel swelling environment, releases said active agent in a controlled continuous manner by diffusion for a predetermined period of time, a method of preparing such a device, and the use thereof to release an active agent into the intended environment of use.

Liquid 2-(2-hydroxy-3-higher branched alkyl-5-methyl-phenyl)-2H-benzotriazole mixtures, stabilized compositions and processes for preparing liquid mixtures

Abstract: Liquid 2-(2-hydroxy-3-higher branched alkyl-5-methylphenyl)-2H-benzotriazole mixtures are prepared by alkylating 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole with a straight chain alkene or with a branched chain alkene of 8 to 30 carbon atoms in the presence of an acidic catalyst at 100°-200° C. The liquid mixtures exhibit outstanding efficacy in protecting organic substrates from light induced deterioration as well as good resistance to loss by volatilization or exudation during the processing of stabilized compositions at elevated temperatures.

Pyridoxine megavitaminosis: an analysis of the early changes induced with massive doses of vitamin B6 in rat primary sensory neurons.

Abstract: The early effects of high toxic doses of vitamin B6 (pyridoxine) on the peripheral sensory neurons were studied in laboratory rats. The animals were treated with 600 mg/kg of pyridoxine hydrochloride by intraperitoneal injection twice daily. Thereafter they were killed by perfusion-fixation at periods ranging from one to 14 days and the tissues were examined by light and electron microscopy. The primary change consisted of the formation of swollen membranous profiles in both the axon hillock and the initial axonal segment of the large dorsal root cytons. This change occurred within 24 hours of exposure, and was followed by an axonal reaction of the nerve cell bodies and by secondary degeneration of their processes. These findings identify the probable target site for pyridoxine toxicity, and establish a simple animal model for studying not only sensory denervation, but also the axonal reaction and secondary degeneration.

Pathology of human african trypanosomiasis with reference to experimental african trypanosomiasis and infections of the central nervous system

Abstract: Les trypanosomes avec leur variation antigenique ont des preferences topographiques a l'interieur de l'hote et a l'interieur d'organes particuliers. Le systeme lymphatique est un site important pour la multiplication. La reponse cellulaire inflammatoire est complexe et se manifeste par une immunodepression. On note des alterations metaboliques. Le role de l'autoimmunite n'est pas clairement defini