Showing papers by "Novartis published in 1986"

Shock and tissue injury induced by recombinant human cachectin.

Abstract: Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators

Abstract: Recently, cDNA sequences have been reported for both human and murine tumor necrosis factor (TNF; cachectin). The coding region of the TNF genes is highly conserved between man and mouse; 80% homology is apparent at the amino acid level. We now observe that a 33-nucleotide sequence, comprised entirely of A and T residues and located in the 3'-untranslated region, is conserved in toto in the murine and human TNF mRNAs. Since the 3'-untranslated region is normally not conserved, we reasoned that this sequence might play a regulatory role. We identified a consensus sequence (TTATTTAT) present in the 3'-untranslated region of both human and mouse TNF mRNAs, as well as the mRNAs encoding human lymphotoxin, human colony stimulating factor, human and mouse interleukin 1, human and rat fibronectin, and most of the sequenced human and mouse interferons. All of these mRNAs, except the lymphotoxin mRNA, lack homology to the TNF mRNAs in the coding region. The consensus sequence is uncommon among mammalian mRNAs in general, but it appears with a frequency greater than chance alone would dictate, suggesting that it may serve a specific regulatory function among the mRNAs in which it is found. It is particularly prevalent among mRNAs encoding proteins related to the inflammatory response.

Enhancement of epidermal regeneration by biosynthetic epidermal growth factor.

Abstract: Epidermal regeneration depends on mitosis and migration of keratinocytes. Epidermal growth factor is known to stimulate growth of keratinocytes in vitro, thus it might be expected to promote wound healing. The results of this study show that topical application of biosynthetic human epidermal growth factor accelerates epidermal regeneration in split-thickness wounds and partial-thickness burns. The significant enhancement of epidermal regeneration suggests the potential for clinical use of epidermal growth factor for accelerating healing of burns, wounds from trauma, diabetic ulcers, skin graft donor sites, and others.

Growth restoration of insulin-deficient diabetic rats by recombinant human insulin-like growth factor I.

Abstract: Insulin-like growth factor I (IGF-I) and insulin stem from a common precursor, are structural homologues, act through similar receptors and elicit insulin-like and growth-promoting effects in vitro and in vivo1,2. Serum IGF-I levels are controlled by growth hormone1, insulin3–6 and nutrition6–10. Insulin-deficient growth-arrested diabetic animals have reduced serum IGF-I levels which are restored towards normal by insulin but not by growth-hormone treatment3–6. Here we show that normal growth of diabetic rats is restored by infusion of recombinant human (rh)IGF-I without normalization of the blood sugar level and that insulin acts via an increase of IGF-I synthesis on growth of diabetic rats. We describe a new mechanism of endocrine control of growth in which IGF-I is the major stimulator at the cellular level. Growth hormone and insulin act mainly by modulating the hepatic synthesis of IGF-I.

Autonomous activation of B and T cells in antigen-free mice.

Abstract: The spleen of adult antigen-free mice contains a sizable proportion (5-15%) of activated cells in all lymphocyte sets, as marked by the membrane expression of immunoglobulins, L3T4 and Lyt-2 antigens. The frequency of activated cells is very high in early post-natal life, and reaches adult levels by 6 weeks of age when it is comparable to that observed in healthy unmanipulated mice raised in conventional conditions. The effector B cell compartment is quantitatively similar in antigen-free mice and specific pathogen-free mice, but the former is deficient in isotype diversification, since IgG- and IgA-secreting cells are drastically reduced. The effector T cell compartment is slightly reduced in number, but is equally competent in providing help or suppression of syngeneic B cells. The results indicate the existence of a compartment of the immune system displaying autonomous self-determined activity which is predominant early in life. This compartment, physically localized to the spleen, appears to be distinct from an antigen-dependent compartment which is essential for the development of peripheral lymphoid organs draining sites of "natural" environmental immunization.

The metabolism of 14C-oxcarbazepine in man.

Abstract: 1. The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects.2. In the 0–6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47 779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (∼4%), and a phenolic derivative of GP 47 779 (<1%).3. The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47 779, and s...

Influence of the vascular endothelium on agonist‐induced contractions and relaxations in rat aorta

Abstract: The influence of the vascular endothelium on agonist-induced contractions and relaxations has been measured using intact segments of rat aorta. Contiguous rubbed segments were used as controls. Angiotensin II, histamine, noradrenaline, U46619 and UK14304 contracted both rubbed and intact tissues. The threshold spasmogenic concentrations of these agonists were lower in rubbed tissues than in intact preparations. The sensitivity and responsiveness of tissues to angiotensin II, histamine, noradrenaline and UK14304 were greater in rubbed than in intact tissues. Acetylcholine and histamine relaxed the established spasms of intact tissues but not those of rubbed preparations, These relaxant effects of acetylcholine were abolished by pre-incubation with haemoglobin. In the presence of prazosin, noradrenaline or UK14304 relaxed established contractions in intact tissues. These effects were antagonized by idazoxan or by pre-incubation with haemoglobin. In intact preparations, idazoxan had no effect on the spasmogenic sensitivity and responsiveness to UK14304. Pre-incubation with haemoglobin augmented the spasmogenic actions of noradrenaline, U46619 or UK14304 in intact tissues, but had no effect on these responses in rubbed preparations. Tissue concentrations of cyclic GMP were greater in intact than in rubbed tissues. A concentration of acetylcholine (10 microM) evoking just maximal mechanical inhibition produced a significant increase in cyclic GMP concentration in intact preparations. However, no detectable changes in cyclic GMP concentration were produced by UK14304 (10 microM) or by acetylcholine (30 nM), concentrations which were equi-effective in inhibiting mechanical activity. In the presence of threshold spasmogenic concentrations of noradrenaline, the contractile effects of angiotensin II were augmented and became comparable to those observed in rubbed preparations. In the presence of greater concentrations of noradrenaline, angiotensin II always produced an additional contraction. It is concluded that the presence of the vascular endothelium limits the spasmogenic action of a variety of agonists. Although spasmogens like noradrenaline and UK14304 can stimulate the release of endothelium-derived relaxing factor (EDRF) via alpha 2-adrenoceptors, the inhibitory effects of EDRF largely result from the spontaneous release of this substance.

Laser lettering on pigmented systems

Abstract: Process for the inscription of organic material of high molecular weight containing at least one radiation-sensitive additive capable of producing a discolouration, characterised in that laser light with a wave length lying in the near UV- and/or visible and/or near IR-region is used as radiation energy and at least one inorganic and/or organic pigment and/or one polymer-soluble dye as additive.

Leukotrienes in inflammation.

Abstract: In conclusion the leukotrienes appear to fulfill the major criteria as mediators of inflammation. They have been shown to be present at a variety of inflammatory sites and to be generated by cells involved in inflammatory sequelae following an inflammatory stimulus. Their effects on the microvasculature and inflammatory cells are consistent with a pro-inflammatory role and the effects of LTB4 in particular on a range of immune responses may indicate a role in the more chronic phases of inflammatory disease. It remains to be conclusively proven that specific inhibition of LT generation or antagonism of LT action will lead to a reduction in inflammatory symptomology in human disease however the data so far provides some hope that drugs with such properties may find a place in the medicinal armamentarium in the relatively near future.

Use of quinoline derivatives for the protection of cultivated plants from herbicides

Abstract: In the method of protecting cultivated plants from the harmful effects of agrochemicals, quinoline derivatives of the formula ##STR1## in which R1, R2 and R3 independently of one another are hydrogen, halogen, nitro, cyano, alkyl or alkoxy, R4, R5 and R6 independently of one another are hydrogen, halogen or alkyl, X is an aliphatic, acyclic, saturated hydrocarbon radical having 1 to 3 carbon atoms and Y is a carboxyl group, or a salt thereof, a mercaptocarbonyl group or a salt thereof, a carboxylic acid ester group, a carboxylic acid thiolester group, an unsubstituted or substituted carboxylic acid amide group, a cyclized, unsubstituted or substituted derivative of a carboxylic acid amide group or a carboxylic acid hydrazide group, or X and Y together are an unsubstituted or substituted tetrahydrofuran-2-one ring, including acid addition salts and metal complexes thereof, or compositions containing such derivatives, are used. Novel quinoline derivatives and their preparation are also described.

Dispensing device for storing and applying at least one liquid or pasty substance

Abstract: A dispensing device comprises a cartridge unit with at least two chambers containing liquid or pasty substances and pistons therein being connected with each other by at least one blade adapted for cutting through a dividing wall, between two chambers and separating their contents, only one piston assembly being required which can be operated with a propellant under excess pressure preferably not exceeding 6 bars. As no piston rod is required the construction of the device is very compact. In a first step for actuating the pistons, the cartridge unit is moved forward toward an exit end of the device bearing a discharge nozzle whereby valves in the device are opened and contents from the cartridge unit are conveyed to the discharge nozzle. After each discharge a restoring element returns the cartridge unit to a rearward end position whereby the valves are closed and no contents can leak from the cartridge.