Showing papers by "Novartis published in 1977"

Function of the Outer Membrane of Escherichia coli as a Permeability Barrier to Beta-Lactam Antibiotics

Abstract: On the basis of a simple theoretical model, the ease of penetration of β-lactam antibiotics through the outer membrane of Escherichia coli was measured. The cell envelope was found to act as a diffusion barrier to both penicillins and cephalosporins. The validity of the model and the cooperative action of cell-bound β-lactamase and outer membrane were further verified by comparing calculated and experimentally determined velocities of β-lactam hydrolysis by intact cells and sonically treated cell suspensions. The results showed good correspondence at five different antibiotic concentrations. Similar conclusions could be drawn from a comparison of β-lactam concentrations on both sides of the outer membrane, calculated from enzyme kinetic measurements and minimal inhibitory concentrations for both a β-lactamase-producing E. coli and its enzyme-negative variant. in the case of benzylpenicillin and cephalothin, however, no correspondence was found. The joint action of several parameters determining the efficacy of penicillins and cephalosporins against β-lactamase-producing E. coli is discussed.

Blockade of presynaptic alpha-receptors and of amine uptake in the rat brain by the antidepressant mianserine.

Abstract: Mianserine (Org GB 94, Tolvon®) is 1, 2, 3, 4, 10, 14b-hexahydro-2-methyl-dibenzo [c, f] pyrazino [1, 3-a] azepine hydrochloride, a new antidepressant drug Its effect on noradrenaline release and its capacity to inhibit amine uptake were investigated Mianserine increased the release of 3H-noradrenaline from field-stimulated cortical slices previously labelled with the tritiated transmitter The assumption that this effect is due primarily to the blockade of the presynaptic noradrenergic α-receptors is supported by the fact that mianserine failed to augment 3H-noradrenaline release further after blockade of the presynaptic α-receptors by phentolamine In the reciprocal experiment, phentolamine failed to augment 3H-noradrenaline release after exposure of the slices to mianserine The hypothesis is further reinforced by the fact that mianserine antagonized the reduction of 3H-noradrenaline release by clonidine in the same manner as the α-blocking drugs phentolamine and phenoxybenzamine Mianserine inhibited noradrenaline uptake in vitro and in vivo (in the rat heart and midbrain-diencephalon synaptosomes from pretreated rats) Only a marginal inhibition of serotonin uptake was observed

Detergent influence on rat-liver galactosyltransferase activities towards different acceptors.

Abstract: 1. Galactosyltransferase activities in postnuclear supernatants and Golgi fractions from rat liver were assayed with two improved and simplified methods, using high- and low-molecular-weight acceptors. Transfer to N-acetylglucosamine was measured after the separation of the reaction product N-acetyllactosamine from all other radioactive molecules (including galactose) on an ion-exchange column partially converted to the borate form. To determine the transfer of galactose to a glycoprotein acceptor we used ovomucoid, which accepts galactose without any previous chemical or enzymic modification. 2. Both enzymic activities were enriched 60–80-fold (compared with the post-nuclear supernatant) in Golgi fractions, which were isolated on two subsequent sucrose gradients and identified morphologically by their high contents of stacked Golgi elements. The two activities could not be resolved by isolation of the Golgi fractions or by detergent solubilization. Each acceptor inhibited the galactose transfer to the other one (up to 95%), presumably because both compete for the same enzyme. 3. The transferase activities were enhanced by the nonionic detergent Triton X-100. The degree of activation depended directly on the amount of Triton bound to the membrane, i.e. the Triton/phospholipid ratio and not the w/v concentration of the detergent in the assay medium. This relationship persisted, regardless of the purity of the Golgi preparation: Half-maximal activation occurred at the same Triton/phospholipid ratio in postnuclear supernatants as well as in isolated Golgi fractions. The activation could not be explained by complete solubilization, because 50% of the fully activated enzyme could still be sedimented (1 h, 100000 ×g). 4. Galactose transfer to the high-molecular-weight acceptor required a higher Triton/phospholipid ratio for half-maximal activation than did the transfer to the monosaccharide N-acetylglucosamine (1 mg/mg compared with 0.5 mg/mg). The degree of activation maximally achieved was much higher with the protein acceptor (400%) than with the sugar (150%). Because both activities are probably due to the same enzyme, it is suggested that these differences in activation reflect properties of the membrane rather than the enzyme, e.g. the presence of a tight diffusion barrier for ovomucoid and the breakdown of this barrier by the detergent.

Papulacandins, a new family of antibiotics with antifungal activity, I. Fermentation, isolation, chemical and biological characterization of papulacandins A, B, C, D and E.

Abstract: Papulacandin, a new antibiotic complex, active against Candida albicans and several other yeasts, was isolated from a strain of Papularia sphaerosperma. The fermentation, isolation, physico-chemical properties and biological activity of the five structurally related papulacandins A, B, C, D and E are reported. Papulacandin B, the main component, was assigned the formula of C47H64O17.

Metal-non-metal transition in silver chalcogenides

Abstract: The paper reviews the crystallographic, optical, magnetic and transport properties of silver chalcogenides Ag2S and Ag2Se. In the low temperature β-phases, the influence of stoichiometry on the respective magnitude of ionic and electronic conductivities is important. In the disordered high-temperature α-phases, the characteristic feature is the statistic distribution of lattice silver ions. This situation is analysed according to the theory established by Mott (e.g. 1974, and Mott and Davis 1971) for amorphous semiconductors. Owing to the disorder, tails appear both in valence and conduction band, and in α-Ag2Se, the bands overlap.

Binding of Thienamycin and Clavulanic Acid to the Penicillin-Binding Proteins of Escherichia coli K-12

Abstract: Thienamycin and clavulanic acid are new beta-lactam derivatives with structures markedly different from those of penicillins or cephalosporins. Both derivatives had the same general mode of action as typical beta-lactam antibiotics since they bound to precisely the same proteins as [(14)C]benzylpenicillin. Thienamycin showed high affinity for penicillin-binding proteins 1, 2, 4, 5, and 6 and a lower affinity for protein 3. Protein 2 had the highest affinity for thienamycin, and concentrations from the minimal morphological change concentration (0.1 mug/ml) up to about 0.6 mug/ml resulted in the conversion of Escherichia coli KN126 into large osmotically stable round cells. Above a concentration of 0.6 mug/ml, rapid cell lysis occurred with the release of the cell contents as spheroplasts. Clavulanic acid showed good affinity for penicillin-binding protein 2, moderate affinity for proteins 1, 4, 5, and 6, and low affinity for protein 3. Protein 2 had the highest affinity for clavulanic acid, and concentrations from the minimal morphological change concentration (30 mug/ml) up to about 50 mug/ml produced a mixture of slightly elongated, swollen, bulging, and lemon-shaped cells. Above a concentration of 50 mug/ml, rapid lysis occurred with production of spheroplasts. The properties of thienamycin and clavulanic acid were compared with those of the penicillins, cephalosporins, and amidinopenicillanic acids.

Properties of polymeric thin films by integrated optical techniques

Abstract: We report an innovative procedure for taking measurements using integrated optical techniques on a number of polymers fabricated into thin film form and used as optical waveguides. Refractive index (including anisotropy), absorption and scattering, and film thickness have been determined by light guiding properties. Techniques for film preparation, including doctor blading, dipping, horizontal flowing, and spinning, are also discussed. The polymers studied are poly(methyl methacrylate), poly(vinyl-formal), polyacrylonitrile, poly(vinyl alcohol), poly(vinyl pyrrolidone), poly(vinyl benzoate), and polystyrene.

Totalsynthese von Humaninsulin. IV. Beschreibung der Endstufen

Abstract: Total synthesis of human insulin. IV. Description of the final steps. Recently a preliminary account was given of a new synthetic pathway leading to human insulin. In the present report the last steps of this synthesis – i.e. as from the unsymmetrical cystine derivative I – are described in detail. I contains the sequences A(14–21) and B(17–30), linked by the disulfide bridge A20-B19. These last steps are: (1) selective removal by pH-controlled acidolysis in trifluoroethanol of N(α)-Trt from leucine B17, (2) completion of the B-chain by coupling with the fragment B(1–16), (3) selective removal by trifluoroethanol of N(α)-Bpoc at tyrosine A14, (4) completion of the A-chain by coupling with the cyclic fragment A(1–13), (5) removal of the acid labile protecting groups, and (6) formation of the disulfide bond A7–B7 from the two S-acetamido-protected cysteine residues by treatment with iodine. As judged by the composition of the reaction mixture the closure of the 85-membered ring proceeds with a cyclization yield of over 70%. From the last step in the synthesis two products were obtained after extensive purification by counter-current distribution: pure human insulin in a yield of 50% and its [D-tyrosine B16]Isomer in a yield of 25%. Although the partial racemization of tyrosine B16 occurred during coupling with sequence B(1–16), the [D-tyrosine B 16]-stereoisomer could only be separated at the endproduct stage. The available evidence indicates that the ease of formation of the disulfide bond A7–B7 does not depend on the precursor molecule already having an insulin-like conformation.

Crosslinkable polymeric compounds

Abstract: The invention relates to organic polymers which can be crosslinked under the action of light and which are suitable for carrying out photomechanical processes. These polymers are photochemically considerably more sensitive than known comparable polymers and their sensitivity can additionally also be further increased by means of a combination with sensitizers. The molecular weight is at least 1,000. The polymers contain, as light-sensitive groups, groups of the formula I ##STR1## wherein R and R 1 independently of one another denote alkyl groups with at most 4 C atoms, or R and R 1 conjointly denote the remaining part of a 5-membered to 6-membered carbocyclic ring.

Methylhistamine: evidence for selective deamination by MAO B in the rat brain in vivo.

Abstract: — A new method has been developed for the separation of histamine and its metabolites after intracisternal injection of [3H]histamine into the rat brain, involving solvent extraction and subsequent thin-layer chromatography. The effect of graded doses of the MAO inhibitors deprenil and pargyline, which at relatively low doses inhibit preferentially the B form (phenethylamine deaminating) of the enzyme, and clorgyline, which mainly inhibits the A form (serotonin, noradrenaline and dopamine deaminating) on the brain levels of intracisternally injected [3H]histamine and its labelled metabolites was studied and compared to MAO A and B activity as determined with the substrates serotonin and phenethylamine, respectively. In addition, the time-course of the effects of a single dose of pargyline (50mg/kg subcutaneously) was investigated. No [3H]imidazoleacetic acid could be detected in any of the control or treated animals. [3H]Histamine accounted for 9–12% of the total extracted radioactivity and this was not altered significantly by pretreatment with any of the MAO inhibitors up to high doses, at which both MAO A and B activities were completely inhibited. In the controls, 40–43% of the total extracted radioactivity was [3H]methylhistamine and 28–30% was [3H]methylimidazoleacetic acid. Deprenil and pargyline caused [3H]methylhistamine levels to increase in a dose-dependent manner up to about 150% of control levels and those of [3H]methylimida-zoleacetic acid to decrease concomitantly to about 10% of control levels. Clorgyline in doses up to 10 mg/kg subcutaneously (s.c.) had no effect on the levels of these two metabolites. The dose-response curves of the effects of deprenil and pargyline on [3H]methylimidazoleacetic acid levels were congruent with those of the MAOI effects on MAO B activity and not with those on MAO A activity. Pargyline (50 mg/kg s.c.) had a long lasting effect on the accumulation of [3H]methylhistamine and [3H]methylimidazoleacetic acid. Recovery occurred within 21 days, and the half-lives observed were 5.3 and 5.6 days, respectively. This compares well to the half-life for the recovery of MAO B activity reported earlier after the same dose of pargyline (5.5 days). These results suggest that methylhistamine is metabolized selectively by MAO B in rat brain. Moreover, the fact that clorgyline, at doses where phenethylamine deamination is already considerably inhibited, did not affect the deamination of methylhistamine, suggests that the latter is an even more selective substrate for MAO B than phenethylamine itself. Therefore, small doses of deprenil (0.3–3 mg/kg s.c.) or pargyline (1–3 mg/kg) can be used to influence histamine catabolism without interfering with catecholamine or serotonin deamination.

Squeeze bottle dispenser with air check valve on cover

Abstract: A squeeze bottle type dispenser has a resiliently collapsible container for the liquid to be dispensed. A cover on the container, said cover means has a flexible resilient central portion flexible outwardly of the cover away from the container. A dispensing valve member on the cover has a dispensing orifice therein, and an interior surface facing into the container. A dispensing valve body is fixed in position within the container adjacent the cover and has an exterior surface complementary in shape to that of the interior surface of the dispensing valve member and with which the interior surface of the valve member tightly engages when the parts of the dispenser are in the non-dispensing positions. The interior of the valve body is hollow and the valve body has product dispensing apertures opening from the hollow interior through the exterior surface thereof and which are normally covered by the valve member when the parts of the dispenser are in the non-dispensing positions. The dispenser has an air return flow path therethrough and a valve therein opening the air return flow path when the pressure on the outside of the container is greater than the pressure on the inside of the container. A dip tube or a collapsible bag within the container is connected to the valve body for delivering liquid to the hollow interior of the valve body when the container is collapsed.

The stabilization of PVC against heat and light

Abstract: The lecture provides a survey on the actual status of the heat and light stabilization of PVC with special emphasis on the mode of action of the stabilizers. In the first part a brief treatment of the most important facts of the thermal degradation of PVC are given, followed by a discussion of some proved specific functions of heat stabilizers by using organotin mercaptide as a typical example. A general concept differentiating preventive and curative stabilizer functions is proposed which seems to be applicable to all types of thermal stabilizers. The second part of the lecture deals with the problematics of light degradation and light stabilization. Some fundamental facts of the light degradation are briefly dealt with and provisions for an enhancement of the light stability are discussed, covering also the implication of the thermal stabilizers.

Method for making reinforced composites

Abstract: A method for the preparation of prepregs comprises I. impregnating a fibrous reinforcing material with a liquid composition containing an epoxide resin, a photopolymerizable compound, and with a heat-activated curing agent for epoxide resins, and Ii. in the absence of a substance which gives rise to a substantial degree of photoinduced polymerization through consumption of epoxide groups, exposing the impregnated material to actinic radiation such that the composition solidifies due to photopolymerization of the said photopolymerizable compound while the epoxide resin remains substantially in the thermosettable state. Preferably the liquid composition also contains a dual-functional substance which has in the same molecule both an epoxide group and a dissimilar group through which the substance can be photopolymerized. The prepreg, optionally after shaping and/or stacking, is heated to cure the epoxide resin and, if used, the photopolymerized dual-functional substance.

Substituted malonic acid derivatives and their use as stabilizers

Abstract: Esters and amides from 4-hydroxy-and 4-amino-polyalkylpiperidines and hydroxybenzylmalonic acids substituted at the central carbon atom with an organic residue, preferably alkyl-, esteralkyl- or phosphonoalkyl-groups, are excellent stabilizers for organic polymers, especially for polyolefins. They protect the polymers as well against light degradation as against thermo-oxidative degradation. The compounds can be prepared by hydroxybenzylation of the corresponding derivatives of substituted malonic acids. Bis-malonic acid derivatives may be obtained from the monomalonics by reaction with formaldehyde.

Biotransformation and pharmacokinetics of acenocoumarol (Sintrom®) in man

Abstract: The absorption, biotransformation and elimination of the anticoagulant acenocoumarol, 3-[α- (4′-nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin, have been studied by oral administration of 12 mg of a14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and the plasma concentration of unchanged drug reached a maximum of 169 and 412 ng/ml, respectively, after 3 hours. The elimination half-life in the two subjects, calculated from the decline between 6 and 24 h, was 8.7 and 8.2 hours. A constant proportion of 98.7% of the drug was bound in vitro to serum proteins over a concentration range of 0.021–8.34 µg/ml, with little interindividual variation. The major portion of the binding was to human serum albumin (97.5%) at two classes of binding sites: association constant K1=1.04×105 l/mole (n1=1) and K2=5.55×103 l/mole (n2=4). In addition to unchanged acenocoumarol, four metabolites were determined in plasma by isotope dilution techniques: the amino-, acetamido-, alcohol1- and alcohol2-metabolites. Of them, the amino-metabolite showed the highest concentration, namely 278 ng/ml, after 6 h in Subject A, and 163 ng/ml after 10 hours in Subject B. Judged from the integrated concentrations, the compounds analyzed accounted for 76 and 89%, respectively, of the total radioactivity in plasma. All the metabolites detected in plasma showed anticoagulant activity when tested in mice. The quantities of the metabolites excreted in urine from 0–120 hours were (Subject A/Subject B): acenocoumarol 0.3/0.2%, amino-metabolite 12.3/7.7%, acetamido-metabolite 19.0/11.1%, alcohol1-metabolite 4.6/9.0%, alcohol2-metabolite 1.7/4.4%, 6-hydroxy-metabolite 6.9/18.3% and 7-hydroxy-metabolite 14.0/22.2%.

Pharmacokinetic studies with chlorthalidone (Hygroton) in man.

Abstract: The kinetics of chlorthalidone in blood and urine were analysed in one group of 6 healthy volunteers after single oral doses of 50, 100 and 200 mg, as well as in a second group of 6 volunteers during and after daily oral doses of 50 mg for 14 days. The mean maximal concentrations recorded in blood 8 h after the three different doses were 3.15 µg/ml (SD±0.52), 5.55±1.58 µg/ml and 7.93±1.40 µg/ml, respectively. Disappearance of chlorthalidone from blood followed an apparent first order type of reaction, the average half life t50 being 49 h (SD 11 h). Total renal elimination of unchanged chlorthalidone amounted to 53.3±8.7%, 46.1±8.4% and 34.0±7.3% of the single 50, 100 and 200 mg doses. Between the 6th and 14th days of daily treatment the concentration at the end of the 24 h dose interval was 7.2±1.4 µg/ml (± 1.4) in blood and 186±44 ng/ml in plasma. Except in the early absorption phase after each dose, the distribution of chlorthalidone between erythrocytes and plasma was constant, the average plasma concentration being 1.38±0.28% (n=75) of the whole blood concentration. At steady state during daily dosing with chlorthalidone 50 mg, the renal elimination of unchanged chlorthalidone within each 24 h dose interval was 57±11.2% of the daily dose. The renal plasma clearance ranged from 46 to 70 ml/min. Following termination of repeated administration the concentration of chlorthalidone in blood decreased with a t50=50±5 h and in plasma with t50=49±4.8 h.

Flame-resistant polymer compositions

Abstract: Flameproofing of aromatic polymers is achieved by adding a synergistic combination of (a) a phosphorus compound and (b) a compound of formula R(CH 2 X) n , wherein R is an aromatic or heterocyclic residue, X is a leaving group and n is at least 2. Preferred phosphorus compounds are esters of phosphoric acid. The flameproofed polymers may contain aromatic groups in the main chain or as side-groups, for instance styrene polymers and copolymers, aromatic polyesters, polycarbonates and polyphenylene oxides.

Pyridyloxy-phenoxy-alkanecarboxylic acid derivatives which are effective as herbicides and as agents regulating plant growth

Abstract: of the Disclosure The present invention concerns new pyridyloxy-phenoxy-alkanecarboxylic acid derivatives of the formula wherein A is hydrogen, halogen, alkyl, alkoxy, cyano, nitro or carbothiamide B is hydrogen, halogen, alkyl, cyano, mono- or dialkylamino, alkoxy-carbonyl or carbothiamide C is hydrogen, halogen, cyano, nitro or carbothiamide D is hydrogen, halogen, alkyl, mono- or dialkylamino R1 is hydrogen, alkyl, alkoxyalkyl or benzyl R is the rest of the acid a salt or an ester, with the proviso that if the pyridine ring is substituted by halogen and/or alkyl and C is also halogen, then the radicals A, B and D must contain no less than two halogen atoms or alkyl radicals. These derivatives have herbicidal and plant-growth regulating activity. - 1a -

Are endogenous C-type viruses involved in the immune system?

Abstract: DNA sequences coding for infectious C-type viruses (oncornaviruses) are present in the genome of normal cells of various species, those best characterised being chicken, mouse, cat and baboon1. Mammalian endogenous viruses, in general, are restricted for growth in their autologous species but replicate in autologous species and are termed xenotropic2. In mice and some other species a further class of endogenous viruses has evolved which is restricted in heterologous cells but replicates in homologous cells, they are termed ecotropic3. Endogenous viral genes are inherited in the germ line and have co-evolved, in general, with non-viral host genes as indicated by evolutionary data4. One explanation for the retention of these genes is that they are involved in physiological functions as proposed by Temin in his protovirus hypothesis5. We have shown previously that B-cell proliferation induced by certain B-cell mitogens is frequently associated with expression of endogenous virus6–10. This has been confirmed by other workers who reported a xenotropic, host range of the mitogen-induced virus11. In contrast to other virus induction methods, mitogen stimulation closely resembles a physiological process, that of antigen stimulation followed by lymphocyte proliferation. Whereas B cells can be induced by mitogens to release virus, we have evidence that T cells are refractory to induction when using T-cell mitogens as well as 5-bromo-2′-deoxyuridine8. These results suggest that the expression of endogenous xenotropic C-type viral genes may be physiologically required for B cells to participate in the immune response. As a test of this hypothesis we examined the effect of antisera directed against xenotropic endogenous C-type virus on the humoral immune response of mice. We show here that such sera are immuno-suppressive.

Epoxide resin mixtures

Abstract: The invention relates to storage-stable, thermosetting mixtures which contain polymaleimides, epoxide compounds having at least one allyl group, and optionally, curing agents for epoxide compounds, and/or curing accelerators for epoxide resin mixtures. These mixtures can be converted by curing into high-polymers which have excellent electrical properties (especially at high temperatures) and very good thermal properties.

Treatment of water

Abstract: A process for the prevention of scale and the inhibition of corrosion which comprises adding to water a hydrolyzed terpolymer of maleic anhydride with vinyl acetate and ethyl acrylate, the molar ratio of maleic anhydride to the other monomers being from 2.5:1 to 5:1, the ratio of vinyl acetate to ethyl acrylate being 1:1 to 2:1, and the molecular weight of the terpolymer being below 1000.

Preparation of phenolic ethylenediaminepolycarboxylic acids

Abstract: A process for the preparation of phenolic ethylenediamine polycarboxylic acids in predominantly the ortho isomeric form which comprises reacting a phenol compound, ethylenediamine, glyoxylic acid and a base, said phenol compound functioning both as a reactant and as the sole solvent for the reaction system. The product can then be isolated or directly reacted with an iron salt to form the corresponding iron chelate.