Showing papers by "Eli Lilly and Company published in 1987"
TL;DR: The primary structure of human insulin-like growth factor II receptor, predicted from the complementary DNA sequence, reveals a transmembrane receptor molecule with a large extracellular domain made up of fifteen repeat sequences and a small region homologous to the collagen-binding domain of fibronectin.
Abstract: The primary structure of human insulin-like growth factor II receptor, predicted from the complementary DNA sequence, reveals a transmembrane receptor molecule with a large extracellular domain made up of fifteen repeat sequences and a small region homologous to the collagen-binding domain of fibronectin. The structural and biochemical features of the IGF-II receptor appear identical to those of the cation-independent mannose-6-phosphate receptor.
851 citations
Patent•
17 Dec 1987TL;DR: In this paper, a 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine were used to prevent suicide.
Abstract: The present invention provides 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine.
201 citations
TL;DR: Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity, indicating the high affinity that buprenorphines has for the kappa receptor results in potent kappa receptors antagonist activity in vivo.
121 citations
TL;DR: A typical procedure and guidelines for conducting the rat in vitro hepatocyte DNA-repair assay for assessing the genotoxic activity of chemical agents are provided.
Abstract: The in vitro rat-hepatocyte DNA-repair assay is a valuable tool in assessing the genotoxic activity of chemical agents. An advantage of the assay is that the target cells themselves are metabolically competent, so that the patterns of metabolic activation and detoxification closely reflect those in the whole animal. This article provides a typical procedure and guidelines for conducting the rat in vitro hepatocyte DNA-repair assay.
115 citations
TL;DR: The results of the present study indicate that mannose-6-phosphate can modulate the interaction of IGF-II to its receptor, and support the hypothesis that a single protein of Mr-250,000 binds both IGF- II and mannoses- 6-ph phosphate.
91 citations
TL;DR: Findings are viewed as evidence that LY163502 can initiate sexual behavior and lower the threshold for ejaculation and as behavioral manifestations of selective dopaminergic autoreceptor activation with low doses and as the disruption of sexual behavior by induction of intense stereotypic behavior with high doses.
Abstract: The effects of selective D2-dopaminergic receptor stimulation with LY163502 on male rat copulatory behavior were evaluated. LY163502 (25 ng/kg to 25Μg/kg s. c.) produced increases in the percentage of sexually inactive rats displaying mounting behavior and ejaculating during the test period. Within this same dose range, LY163502 administration induced an increase in the percentage of non-ejaculator rats that were capable of ejaculation. These findings are viewed as evidence that LY163502 can initiate sexual behavior and lower the threshold for ejaculation. The effects of LY163502 were further evaluated in rats that were capable of ejaculation during the test period. LY163502 (25 ng/kg to 25Μg/kg s. c. or p. o.) induced significant reductions in ejaculatory latency. These effects were blocked by prior treatment with centrally active dopaminergic antagonists, RO 22-1319 and sulpiride, but not with a peripherally active antagonist, domperidone. LY163502 administration was also found to inhibit sexual behavior in low doses of 25 pg/kg −10 ng/kg s. c. and in a much larger dose of 25 mg/kg s. c. These inhibitory effects are viewed as behavioral manifestations of selective dopaminergic autoreceptor activation with low doses and as the disruption of sexual behavior by induction of intense stereotypic behavior with high doses.
90 citations
TL;DR: Several observations were made concerning protoplast formation and handling which made the transformation procedure more efficient and allowed a greater proportion of protoplasts to regenerate to viable walled cells.
Abstract: A hybrid gene, IPNSp/HPTorf, was constructed by placing an 850 bp sequence of Cephalosporium acremonium DNA next to the 5' end of a bacterial open reading frame, HPTorf. The sequence was obtained as an 850 bp NcoI restriction fragment from the 5' non-coding region of the C. acremonium isopenicillin N synthetase (IPNS) gene. The HPTorf was obtained from a bacterial gene that coded for a hygromycin B phosphotransferase (HPT). Plasmids that contained IPNSp/HPTorf transformed C. acremonium to a stably maintained hygromycin B resistant phenotype. Southern analysis of total DNA from transformants demonstrated multiple integrations of the transforming DNA in the high molecular weight DNA of most transformants, but single integrations were observed in a few transformants. The number of transformants per microgram of DNA was about 100 times greater than for plasmids that contained the HPTorf without any juxtaposed eucaryotic promoter sequence. Plasmids with the promoterless HPTorf and plasmids with a truncated S. cerevisiae phosphoglycerate kinase promoter juxtaposed to the HPTorf transformed C. acremonium at equivalent low frequencies. Transformation of C. acremonium with linearized plasmid DNA produced at least 2-3 fold more transformants than the corresponding circular molecule. Several observations were made concerning protoplast formation and handling which made the transformation procedure more efficient and allowed a greater proportion of protoplasts to regenerate to viable walled cells. Plasmids were constructed that contained both the IPNSp/HPTorf and additional elements: fragments of C. acremonium ribosomal DNA (rDNA), or a fragment of C. acremonium mitochondrial DNA possessing activity as an autonomous replication sequence (ARS) in S. cerevisiae, or putative transcriptional termination/polyadenylation signals from the IPNS gene. These plasmids transformed C. acremonium at frequencies experimentally equivalent to those containing IPNSp/HPTorf without any of these additional elements.
87 citations
87 citations
TL;DR: Several bicyclic pyrazolidinones were synthesized as γ-lactam analogs of the β-Lactam antibiotics and two of these compounds exhibited in vitro antibacterial activity, and thus constitute a new class of antibacterial agents as mentioned in this paper.
86 citations
TL;DR: The results demonstrate the feasibility of using CAMAC for multivariable drug delivery, but they indicate the need for further work before clinical applications are attempted.
Abstract: An adaptive algorithm (CAMAC, control advance moving average controller) to control multiinput/multioutput physiological systems has been implemented and tested. The algorithm is a self-tuning controller that determines the input on the basis of the expected difference between the output and desired output at a time interval equal to or greater than the system dead time. The algorithm was used to simultaneously control mean arterial pressure and cardiac output in anesthetized dogs by the simultaneous computer-controlled infusion of sodium nitroprusside and dobutamine. The results demonstrate the feasibility of using CAMAC for multivariable drug delivery, but they indicate the need for further work before clinical applications are attempted.
81 citations
TL;DR: Immunocytochemistry studies showed that mast cell neoplasms reacted with avidin and, therefore, were positive, even on negative control sections, and neuron-specific enolase and vimentin reacted strongly on all amelanotic melanomas and transmissible venereal tumors examined.
Abstract: Sixty-five canine skin neoplasms studied using immunocytochemistry, included 22 histiocytomas, 18 amelanotic melanomas, 14 cutaneous lymphosarcomas, six mast cell tumors, and five transmissible venereal tumors. Formalin-fixed, paraffin-embedded sections were stained using the avidin-biotin-peroxidase complex (ABC) immunoperoxidase technique for reactivity with S-100 protein, kappa and lambda immunoglobulin light chains, alpha-1-antitrypsin, alpha-1-antichymotrypsin, leukocyte common antigen (LCA), neuron-specific enolase, keratin, cytokeratin, muramidase, and vimentin. Detection of S-100, kappa and lambda light chains, neuron-specific enolase, and vimentin were most useful for screening these neoplasms. None of the markers examined was consistent in staining histiocytomas. While reactivity of S-100 (ten cases) and neuron-specific enolase (ten cases) was detected in some amelanotic melanomas, lambda light chain immunoglobulin (eight cases) was relatively consistent in cutaneous lymphomas. Mast cell neoplasms reacted with avidin and, therefore, were positive, even on negative control sections. Vimentin reacted strongly on all amelanotic melanomas and transmissible venereal tumors examined. These antibodies are helpful adjuncts in the differential diagnosis of canine skin tumors.
TL;DR: An isocratic reversed-phase high-performance liquid chromatographic method for the determination of human growth hormone (HGH) purity is described, which offers superior resolution of HGH-related substances from unmodified HGH when compared to a number of alternative Chromatographic and electrophoretic techniques.
TL;DR: Agents that inhibit selectively the neuronal reuptake of serotonin but not catecholamines, and that do not interact directly with neurotransmitter receptors, can have antidepressant activity clinically.
Abstract: Agents that inhibit selectively the neuronal reuptake of serotonin but not catecholamines, and that do not interact directly with neurotransmitter receptors, can have antidepressant activity clinically. Their antidepressant action presumably is initiated by enhanced serotonergic input to other neuronal systems in brain, which leads to primary and secondary (adaptive) changes in neurotransmission and results in remission of depressive symptoms.
TL;DR: Data demonstrate that polyacrylamide gel electrophoresis is not a valid method for measuring this dimer and that size‐exclusion chromatography under aqueous conditions is required.
Abstract: A dimer of biosynthetic human growth hormone (HGH) has been isolated and characterized. This entity, which is the predominant dimeric species in biosynthetic HGH, is chemically identical to monomeric HGH and exists in a noncovalent dimeric form which is dissociated to monomeric HGH on polyacrylamide electrophoresis gels or in aqueous solutions containing 30% acetonitrile. This substance, found in all production lots of pituitary HGH, biosynthetic HGH, and biosynthetic methionyl HGH examined, is much less biopotent than monomeric HGH and can be distinguished from monomeric HGH by a monoclonal antibody. These data demonstrate that polyacrylamide gel electrophoresis is not a valid method for measuring this dimer and that size-exclusion chromatography under aqueous conditions is required.
TL;DR: A new macrolide antibiotic, EL-870, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin, has been prepared by chemical modification of desmycosIn vitro, against selected animal bacterial pathogens, it inhibited growth of Pasteurella multocida and other bacteria at levels of 6.25 micrograms/ml or less.
Abstract: A new macrolide antibiotic, EL-870, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin, has been prepared by chemical modification of desmycosin. In vitro, against selected animal bacterial pathogens, it inhibited growth of Pasteurella multocida, Pasteurella haemolytica, Mycoplasma hyopneumoniae, Actinobacillus pleuropneumoniae, Streptococcus suis, Actinomyces pyogenes and certain other bacteria at levels of 6.25 micrograms/ml or less. In general, the MICs for Gram-negative enteric bacteria have been greater than 50 micrograms/ml. Concentrations equivalent to 4 X the MIC value were bactericidal for Pasteurella sp. EL-870 had other antibacterial properties which were characteristic of macrolide antibiotics.
TL;DR: Two plasmids containing DNA fragments from the carbomycin(Cb)-producing strain Streptomyces thermotolerans were identified in Streptomeces griseofuscus based on their ability to confer resistance to Cb, and extensive homology was revealed, suggesting that carB also encodes an RNA methylase.
Patent•
24 Feb 1987TL;DR: In this article, an invention for promoting the rate and improving the quality of wound healing by topically applying insulin-like growth factor-II to the wound was described, where the authors described a method for applying the growth factor to promote wound healing.
Abstract: There is herein described an invention for promoting the rate and improving the quality of wound healing by topically applying insulin-like growth factor-II to the wound.
TL;DR: The data indicate that the decrease in male sexual behavior and the infertility associated with exposure to fenarimol were, most likely, due to inhibition of aromatase activity within the central nervous system.
TL;DR: The Wellcome Research Laboratories and Eli Lilly and Co., Bldg. 240, Rm.
Abstract: J Wellcome Research Laboratories, 3030 Cornwallis Road, Research Triangle Park, NC 27709 (U.S.A.), 2 National Toxicology Program, NIEHS, P.O. Box 12233, Research Triangle Park, NC 2 7709 (U.S.A.), 3 Sitek Research Laboratories, 12111 Parklawn Drioe, Rockoille, M D 20852 (U.S.A.), 4 Environmental Protection Agency, MD 68, Research Triangle Park, NC 27711 (U.S.A.), 5 The Upjohn Company, Kalamazoo, M1 49001 (U.S.A.) and 6 Eli Lilly and Co., Bldg. 240, Rm. 228, Greenfield, I N 46140 (U.S.A.)
TL;DR: The biological activity of this recombinant human IGF-II was measured in a competitive protein binding assay for IGF- II and by its ability to stimulate amino isobutyric acid uptake and protein synthesis in NCTC 2414 fibroblast cultures.
Abstract: Human Insulin-like growth factor II (IGF-II) was produced in Escherichia coli as a 113 amino acid chimeric protein, LE1-Met-IGF-II consisting of 45 N-terminal amino acids from the E. coli trp leader peptide and the trpE polypeptide, and 67 C-terminal amino acids for IGF-II. High-level expression of the fusion protein, LE1-Met-IGF-II, was obtained with pCZ21, a plasmid containing a thermoinducible runaway replicon and the kanamycin resistance marker from Tn5. In E. coli, LE1-Met-IGF-II formed granules that were isolated and cleaved with cyanogen bromide to liberate IGF-II. IGF-II was sulfitolyzed, purified by anion exchange chromatography, refolded through a disulfide interchange reaction, and further purified by reverse-phase HPLC and gel filtration. The biological activity of this recombinant human IGF-II was measured in a competitive protein binding assay for IGF-II and by its ability to stimulate amino isobutyric acid uptake and protein synthesis in NCTC 2414 fibroblast cultures.
TL;DR: This series of 11 clinical and experimental cases identifies an apparent species-specific, dose-related, primary pulmonary toxicity of cisplatin in cats.
Abstract: Cisplatin (cis-diamminedichloroplatinum; Platinol, Bristol, Syracuse, NY) was administered to 11 cats, divided into three groups of experimental and clinical patients. In group 1, cisplatin was administered at a dose of 60 mg/m2 to four cats. In an attempt to avoid renal toxicity, saline diuresis was induced by administering 0.9% saline solution intravenously at a rate of 20 ml/kg/hr for 4 hours before and 2 hours after cisplatin administration. All four cats became dyspneic and died 48-96 hours after cisplatin administration. Postmortem findings included severe hydrothorax, pulmonary edema, and mediastinal edema. In group 2, four experimental cats entered a trial comparing the effects of saline diuresis and cisplatin (60 mg/m2) with the effects of saline diuresis and placebo (0.9% saline solution). The cats in the saline control group remained completely normal, while the cats that received cisplatin developed clinical signs and gross postmortem pulmonary changes identical to those in the first group of cats. Histopathologic examination showed that the alveolar septa were thickened and congested, and contained macrophages, occasional neutrophils, thrombi, and small foci of necrosis and fibrin. Microangiopathic changes were seen in the alveolar capillaries. In the third group, three additional cats were treated with a lower dose of cisplatin. Two cats that received 40 mg/m2 of cisplatin developed pulmonary changes similar to, but less severe than, those seen in the cats that received the higher dose of cisplatin. One cat treated with 20 mg/m2 of cisplatin showed no pulmonary changes ante mortem or post mortem. This series of 11 clinical and experimental cases identifies an apparent species-specific, dose-related, primary pulmonary toxicity of cisplatin in cats.
Journal Article•
TL;DR: Neither the potency nor maximum response of these agonists in contracting the rat stomach fundus correlated with the affinity of agonists at 5HT1A, 5Ht1B or5HT1C binding sites, suggesting that these agents have little, if any, affinity for the serotonergic receptor-mediating contraction in the fundus.
Abstract: Serotonin (5HT) is a potent agonist in contracting the rat stomach fundus although the nature of the receptor mediating the response has not been established. The present study was designed to explore the possibility that 5HT-induced contractions in the rat stomach fundus were mediated by interaction with receptors identical with either 5HT1A, 5HT1B or 5HT1C binding sites or 5HT3 receptors. Contractile concentration-response curves for several 5HT agonists [5-carboxamidotryptamine, TR3369, MK212, quipazine, RU 24969, 8-hydroxy-2-(di-n-propylamino)tetralin, TVXQ7821 and BEA 1654CL] were obtained in the rat stomach fundus. However, neither the potency nor maximum response of these agonists in contracting the rat stomach fundus correlated with the affinity of agonists at 5HT1A, 5Ht1B or 5HT1C binding sites. These agonists were interacting with 5HT receptors in the fundus based on the ability of 1-(1-naphthyl) piperazine (10(-7) M) to antagonize the contractile response of the relatively potent agonists. TVXQ7821 and BEA 1654Cl did not produce a marked contractile response in the fundus and also did not antagonize the contractile response to 5HT, suggesting that these agents have little, if any, affinity for the serotonergic receptor-mediating contraction in the fundus. The putative 5HT1A-selective receptor antagonists, WB4101 and spiroxatrine, did not block 5HT-induced contractions in the rat stomach fundus in concentrations consistent with their affinity at 5HT1A binding sites. The nonselective 5HT1A and 5HT1B receptor antagonist, cyanopindolol, also did not block 5HT-induced contractions in the rat stomach fundus.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is suggested that chondrocyte death was the initial important event which led to progressive severe cartilage degeneration in this model.
Abstract: The articular cartilage from femorotibial joints of partial medial meniscectomized male guinea pigs was evaluated at 24, 48, 72, and 96 hours post-surgery to determine the sequential histopathologic and ultrastructural alterations. At 24 hours post-surgery, histopathologic alterations were in the superficial and middle layers and consisted of degeneration and necrosis of chondrocytes and minimal decreased intensity of toluidine blue matrix staining. Changes in chondrocytes and matrix became progressively more extensive 48 hours after surgery. Ultrastructurally, the changes in the superficial matrix appeared to be the result of loss of the fine granular material interspersed between collagen fibers. At 72 and 96 hours post-surgery, chondrocyte loss was extensive and surface fibrillation was seen. These findings suggested that chondrocyte death was the initial important event which led to progressive severe cartilage degeneration in this model.
TL;DR: The beta-binomial distribution has been proposed as a model for the incorporation of historical control data in the analysis of rodent carcinogenesis bioassays but the moment and maximum likelihood estimates are deficient, so a stabilized moment estimator is proposed.
Abstract: The beta-binomial distribution has been proposed as a model for the incorporation of historical control data in the analysis of rodent carcinogenesis bioassays. Low spontaneous tumor incidences along with the small number and sizes of historical control groups combine to make the moment and maximum likelihood estimates of the beta-binomial parameters deficient. We therefore propose a stabilized moment estimator for one of the parameters. The stabilized moment estimator is similar to the ridge regression estimator and introduces a shrinkage parameter. Computer simulations were run to examine the behavior of the stabilized moment estimator. The effect of the stabilized moment estimator on the score test for dose-related trend is considered both on simulated data and on an example from the literature.
TL;DR: The hybrid-hybrid is a bispecific monoclonal antibody recognising both the tumour-associated antigen carcinoembryonic antigen (CEA) and the cytostatic vinca alkaloid donor lymphocytes.
Abstract: Recent developments of hybridoma technology have allowed us to prepare a bispecific monoclonal antibody recognising both the tumour-associated antigen carcinoembryonic antigen (CEA) and the cytostatic vinca alkaloids. The yields of the hybrid-hybrid 28.19.8 monclonal after affinity chromatography purification are close to 50% of the total Ig produced.
TL;DR: From the patterns of restriction enzyme digestion of chromosomal DNA observed in the series of mutants that became progressively less restricting, it was suggested that wild type S. fradiae normally expresses modification systems similar or analogous to PstI, XhoI, ScaI and EcoRI.
Abstract: Streptomyces fradiae JS85 is a mutant defective in tylosin production and an efficient recipient for conjugal transfer of tylosin genes. JS85 was mutagenized with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and derivatives defective in restriction were isolated by sequential selection for increased transformability by several plasmid DNAs. From the number of mutation and selection cycles required to eliminate most restriction, it was estimated that wild type S. fradiae expressed at least five restriction systems. From the patterns of restriction enzyme digestion of chromosomal DNA observed in the series of mutants that became progressively less restricting, it was suggested that wild type S. fradiae normally expresses modification (and presumably restriction) systems similar or analogous to PstI, XhoI, ScaI and EcoRI. The least restricting mutant of S. fradiae was readily transformable by many plasmids, including a bifunctional cosmid vector containing a large insert of Streptomyces DNA.
TL;DR: Fluoxetine (IP) decreased this palatability-induced excessive consumption in a dose-related manner and may relate to previously reported effects of fluoxettine on food consumption.
Abstract: Non-deprived rats were allowed 1-h access to a range of saccarin solutions from 0.001 to 0.1 M Na saccharin. Compared to a group of rats drinking tap water, the rats drinking the saccharin solutions ingested a great deal more fluid, with as much as 24–30 ml consumed of the 0.01 M concentration, compared to 3–5 ml in controls. Fluoxetine (IP) decreased this palatability-induced excessive consumption in a dose-related manner. Effects of 10 mg/kg fluoxetine were apparent for 48 h after injection. This effect on palatability-induced ingestion may relate to previously reported effects of fluoxetine on food consumption.
TL;DR: The sequential histopathologic alterations in femorotibial joints of partial meniscectomized male and female guinea pigs were evaluated and it was found that Milder, more slowly progressive lesions in the contralateral leg may be amenable to therapeutic intervention.
Abstract: The sequential histopathologic alterations in femorotibial joints of partial meniscectomized male and female guinea pigs were evaluated at 1, 2, 3, 6, and 12 weeks post-surgery. Foci of moderate to severe cartilage degeneration were present in the medial tibial plateau and femoral condyle of the operated leg by 1 week post-surgery. At 2 weeks post-surgery, the cartilage degeneration in the operated legs was more extensive and there was evidence of early chondrophyte formation on the medial side of either the femur or tibia in three animals. Changes were progressively more severe at 3,6, and 12 weeks. Focal areas of minimal to mild cartilage degeneration were in the medial tibial plateau of the contralateral nonoperated leg in some animals at 3 weeks post-surgery and in all animals at 12 weeks post-surgery. Changes in the contralateral leg of meniscectomized guinea pigs have not been described previously. Since cartilage degeneration was often severe by 1 week post- surgery, the model has limited utility for testing agents designed to modify the degenerative process in the operated leg. Milder, more slowly progressive lesions in the contralateral leg may be amenable to therapeutic intervention. Osteoarthritis (OA) is a common affliction of aged human and some domestic animal specie^.^-^ Sponta- neous and experimental animal models of OA allow investigation of pathogenesis and effects of chemo- therapeutic agents on disease progression. Experimental degenerative joint disease has been in- duced by a variety of different procedures in various animal species. Surgical models of OA using collateral ligament transection, partial or complete meniscecto- my, cruciate ligament transection, or various combi- nations thereof have been described in the dog, rabbit, and guinea pig. The guinea pig is smaller and requires less space for housing. Also, less compound would be required than if dogs or rabbits were te~ted.~-~.~~J~ In guinea pigs, medial collateral ligament and anterior cruciate transection with partial medial meniscectomy resulted in severe lesions at 14 weeks post-surgery.13 Minimal arthritic changes were present at 2 1 weeks in guinea pigs in which only the anterior cruciate and collateral ligaments were transected. Lesions were not described in the contralateral nonoperated knees of animals in either group, nor was any information given about the progression of the disease (i.e., whether the lesions were slowly progressive to the ultimate severity described or whether the cartilage degeneration was rapid following surgical intervention). Since osteoar- thritis is generally thought to be a slowly progressive disease, knowledge of the rapidity of disease progres- sion in animal models is important in determining the suitability of models for study of the degradative pro- cesses which occur. In order to better characterize the development of OA in the guinea pig and to determine the suitability of this model of OA for the screening of potential che- motherapeutic agents, the present study was designed to determine the sequential histopathologic alterations in the operated and contralateral nonoperated femo- rotibial joints of partially meniscectomized male and female guinea pigs at 1, 2, 3, 6, and 12 weeks post- surgery.
TL;DR: The data suggest that differences in ionophore accumulation by IS and IR isolates of E. tenella might reflect differences in membrane chemistry and that these differences are responsible for the expressions of resistance that were observed in these studies.