Showing papers by "Eli Lilly and Company published in 1986"

Protection of cattle against foot-and-mouth disease by a synthetic peptide.

Abstract: A chemically synthesized peptide consisting essentially of two separate regions (residues 141 to 158 and 200 to 213) of a virus coat protein (VP1) from the O1 Kaufbeuren strain of foot-and-mouth disease virus was prepared free of any carrier protein. It elicited high levels of neutralizing antibody and protected cattle against intradermolingual challenge by inoculation with infectious virus. Comparative evaluation of this peptide with a single-site peptide (residues 141 to 158) in guinea pigs suggests the importance of the VP1 carboxyl terminal residues in enhancing the protective response.

Minimum Hellinger Distance Estimation for Multivariate Location and Covariance

Abstract: The Hellinger distance between a nonparametric density estimator and a model family is minimized to produce estimates of location and covariance in multivariate data. With suitable restrictions on the density estimators and the model family, these minimum Hellinger distance estimators (MHDE's) are shown to be affine invariant, consistent, and asymptotically normal. The robustness of the MHDE as measured by the breakdown point compares favorably against the previously studied M-estimators. Monte Carlo results suggest that the MHDE's are an attractive robust alternative to the usual sample means and covariance matrix.

Cryptosporidium: Its biology and potential for environmental transmission

Abstract: Protozoans of the genus Cryptosporidium are small (2 to 6 μm, depending on life cycle stage) coccidian parasites that reside within the microvillous region of the mucosal epithelium of man and a variety of animals. Infections with Cryptosporidium spp. were considered rare in animals, and in man they were thought to be the result of a little‐known opportunistic pathogen outside its normal host range. Our concept of Cryptosporidium has changed within the past 4 years to that of a significant and widespread cause of diarrheal illness in several animal species, especially calves and humans. In immunocompetent humans, this protozoan may produce a mild to severe diarrheal illness lasting from several days to more than 1 month. In immune‐deficient persons, especially those with the acquired immune deficiency syndrome (AIDS), cryptosporidiosis usually presents a prolonged, life‐threatening, cholera‐like illness. Treatment of cryptosporidiosis, especially in immune‐deficient persons, has been for the most part uns...

Drug localisation and growth inhibition studies of vindesine-monoclonal anti-CEA conjugates in a human tumour xenograft.

Abstract: The distribution of tritiated vindesine (3H-VDS) was studied in the tissues and tumours of athymic mice bearing a human colorectal tumour xenograft. Selective tumour localisation was obtained when 3H-VDS was injected as a conjugate with a monoclonal anti-CEA antibody (11.285.14) but not as a conjugate with a non-binding monoclonal IgG1 (Ag8) or as free succinoyl-VDS. The amounts of VDS that localised in the tumour following injections of 3H-VDS-11.285.14 increased in proportion to the amount injected, over a wide dose range. Conjugates prepared using the Fab fragments of 11.285.14 showed no evidence of selective tumour uptake in comparison with normal tissues.

Selective chemical removal of a protein amino-terminal residue

Abstract: The invention relates to a process and compounds useful therein for producing a compound having an amino acid sequence defining a biologically active peptide or protein from a compound of the formula H--X--Pro--Peptide in which X is the residue of a naturally occurring amino acid and Peptide is a sequence of amino acids defining a biologically active peptide or protein, which comprises subjecting H--X--Pro--Peptide to conditions under which a diketopiperazine of the H--X--Pro-- moiety is formed with accompanying cleavage and release of Peptide.

Novel glycopeptide derivatives

Abstract: Novel glycopeptide antibiotics of formula (I) can be prepared from the glycopeptide antibiotics vancomycin, A51568A, A51568B, M43A and M43D by reaction with a ketone or aldehyde followed, if appropriate, by reduction. The new glycopeptide derivatives are useful antibacterial agents.

Treatment of obesity with aryloxyphenylpropylamines

Abstract: 3-Aryloxy-3-phenylpropylamines and acid addition salts thereof are useful in blocking uptake of monoamines by brain neurons, and are thus effective in treating disorders of sleep, sexual performance, appetite, muscular function, and pituitary function.

Method of isolating antibiotic biosynthetic genes

Abstract: The present invention is a method for isolating antibiotic biosynthetic genes. To practice the method, an antibiotic resistance-conferring DNA segment is labelled and used as a probe to find, via DNA hydridization, homologous DNA in a genetic library which comprises chromosomal and plasmid DNA of an antibiotic-producing organism. Individual vectors of the genetic library which hybridize to the antibiotic resistance-conferring gene, and which comprise ˜1-45 kb of contiguous DNA from the antibiotic-producing organism, which also comprise an antibiotic biosynthetic gene. The present method is exemplified by using the erythromycin resistance-conferring gene of Streptomyces erythreus to clone the erythromycin biosynthetic pathway from the same organism. The erythromycin biosynthetic pathway isolated with the present method synthesizes erythromycin when introduced into S. lividans TK23.

Cloning and expression of a tylosin resistance gene from a tylosin-producing strain of Streptomyces fradiae.

Abstract: A gene conferring high-level resistance to tylosin in Streptomyces lividans and Streptomyces griseofuscus was cloned from a tylosin-producing strain of Streptomyces fradiae. The tylosin-resistance (Tylr) gene (tlrA) was isolated on five overlapping DNA fragments which contained a common 2.6 Kb KpnI fragment. The KpnI fragment contained all of the information required for the expression of the Tylr phenotype in S. lividans and S. griseofuscus. Southern hybridization indicated that the sequence conferring tylosin resistance was present on the same 5 kb SalI fragment in genomic DNA from S. fradiae and several tylosin-sensitive (Tyls) mutants. The cloned tlrA gene failed to restore tylosin resistance in two Tyls mutants derived by protoplast formation and regeneration, and it restored partial resistance in a Tyls mutant obtained by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) mutagenesis. The tlrA gene conferred resistance to tylosin, carbomycin, niddamycin, vernamycin-B and, to some degree, lincomycin in S. griseofuscus, but it had no effect on sensitivity to streptomycin or spectinomycin, suggesting that the cloned gene is an MLS (macrolide, lincosamide, streptogramin-B)-resistance gene. Twenty-eight kb of S. fradiae DNA surrounding the tlrA gene was isolated from a genomic library in bacteriophage lambda Charon 4. Introduction of these DNA sequence into S. fradiae mutants blocked at different steps in tylosin biosynthesis failed to restore tylosin production, suggesting that the cloned Tylr gene is not closely linked to tylosin biosynthetic genes.

Toxicity of fluridone to aquatic invertebrates and fish

Abstract: The acute and chronic toxicities of the herbicide fluridone to aquatic invertebrates and fish were evaluated. The acute median lethal concentrations (LC50s) of fluridone were 4.3 ± 3.7 mg/L (x±SD) for invertebrates (n = 15) and 10.4±3.9 mg/L for fish (n = 28). In chronic studies, no effects were detected when daphnids (Daphnia magna) were continuously exposed to fluridone concentrations of 0.2 mg/L or less for 32 d, amphipods (Gammarus pseudolimnaeus) to 0.6 mg/L or less for 60 d or midge larvae (Chironomus plumosus) to 0.6 mg/L or less for 30 d. Fathead minnows (Pimephales promelas) were not affected by continuous exposure to fluridone concentrations of 0.48 mg/L or less over their life cycle. The growth and survival of channel catfish (Ictalurus punctatus) were not adversely affected by continuous exposure to fluridone concentrations of 0.5 mg/L or less for 60 d after hatching. The channel catfish accumulated fluridone concentrations two to nine times greater than that in the water. The recommended application rate of 1 lb/acre of fluridone to a pond with an average depth of 3 ft provides a theoretical concentration of 0.1 mg/L. Thus, an initial fluridone concentration of 0.1 mg/L or less is recommended to control weeds in ponds. Consequently, fluridone is not expected to have adverse effects on the species tested or on similar nontarget aquatic organisms.

Orally administerable sustained release pharmaceutical formulations

Abstract: This invention provides orally administerable pharmaceutical formulations having a semi-solid matrix containing a hydrophilic substance capable of creating channels in a hydrophobic carrier matrix thereby providing a sustained rate of release of an active agent from the formulation.

A47934, a novel glycopeptide-aglycone antibiotic produced by a strain of Streptomyces toyocaensis taxonomy and fermentation studies.

Abstract: A47934, a novel glycopeptide-aglycone antibiotic, is produced by a strain of Streptomyces toyocaensis, NRRL 15009. A47934 is unique among reported glycopeptides in that it contains a sulfate ester. Like several other glycopeptides, the majority of the A47934 produced remained associated with the producing biomass, from which it could be released into aqueous media by alkalization. Antibiotic biosynthesis was depressed when initial levels of phosphate phosphorus in the medium exceeded the normal level of 35 micrograms/ml. Enrichment of the fermentation medium with tyrosine depressed A47934 yields while enrichment with p-hydroxyphenylglycine or p-hydroxyphenylglyoxylic acid stimulated antibiotic biosynthesis.

A review of the genus Caryospora Léger, 1904 (Apicomplexa: Eimeriidae)

Abstract: The genus Caryospora (Apicomplexa, Eimeriorina) contains 30 species of coccidia that develop primarily in reptiles and predatory birds. Recent studies have shown that some species of Caryospora are heteroxenous, with both asexual and sexual phases of parasite development occurring in the intestinal epithelium of a predatory reptile or bird and in dermal connective tissues of rodents. The life-cycle of these Caryospora spp. is distinct from all known genera of the Eimeriidae. In this paper we present a review of and redefine the genus Caryospora, present succinct taxonomic descriptions, synonyms and lapsi, and provide line drawings (if available) of oocysts of each of the described species. ac]19841022

Induction and reversibility of thyroid proliferative changes in rats given an antithyroid compound.

Abstract: Sixty Fischer 344 rats were fed a diet containing 90 ppm methimazole, a known antithyroid compound. Following exposure to the test compound, groups of ten animals were terminated at 1, 3, and 6 months. Similar groups of ten treated animals were given control diet for a reversibility period of 2, 3, and 6 months, respectively. Groups of ten control rats were terminated after 1, 3, 6, and 12 months. Except for the expected effect on body weight, the treated animals had no physical signs of toxicity. The weight of thyroids increased with the duration of exposure, becoming in males after 6 months about ten times the weight of thyroids from control rats. Thyroids of treated rats after 1 and 3 months had a diffuse homogeneous hypertrophy and hyperplasia of follicular cells, decreased colloid, and increased vascularity. After 6 months' exposure to the antithyroid compound, there was diffuse hyperplasia but also a heterogeneity in the size and morphology of follicles, protrusion of follicular tissue through the gland capsule and into vascular spaces, and the development of follicular nodules. Treated rats placed on control diet, allowing for reversibility, had thyroids which were decreased in size with large follicles and flattened epithelium, and a complete remodeling of most nodules with no evidence of progression. Although the nodules produced after prolonged administration of the antithyroid compound had many of the characteristics of neoplasia, the biologic behavior supports the diagnosis of nodular hyperplasia. Antithyroid compounds suppress thyroid hormone production and secretion. By a classic feedback control on the hypothalamus and pituitary, these compounds produce an increased secretion of thyroid stimulating hormone (TSH).2,3,5,11,17,23.29,33,34 The size, function, and morphology of the thyroid are quantitatively con- trolled by TSH." The thyroid has an enormous po- tential for proliferation, dependent upon the degree and duration of TSH production. 11~17~19 The follicular cell height varies with the degree of TSH stimulation, becoming tall columnar when active and flattened when lxZ7 Active follicles have decreased colloid, and inactive follicles have increased colloid. Following prolonged administration of antithyroid compounds, thyroid neoplasms have been reported in ro- Quantification of the functional and structural thy- roid changes in the rat given an antithyroid compound has recently been These investigators found a drop to below detection limits for thyroid hormones within 7 days; and over a 5-month period a fivefold increase in TSH, a 12-fold increase in thyroid weight, and a ninefold increase in the number of thyroid cells. The development of vascularization during thyroid hy- perplasia starts prior to the growth of follicular Thyroid follicular hyperplasia, especially nodular hyperplasia, is difficult to distinguish from neopla-

Comparison of the effects of pinacidil and its metabolite, pinacidil-N-oxide, in isolated smooth and cardiac muscle

Abstract: The effects of pinacidil and its major metabolite, pinacidil-N-oxide, were compared in isolated smooth and cardiac muscle preparations. Wide variation occurred in the sensitivity of different smooth muscle preparations to the relaxant effect of pinacidil. Relaxant sensitivity of pinacidil was greatest in the one vascular preparation examined, the rat aorta, where the ED50 for pinacidil was approximately 0.5 μM. Pinacidil was equally potent in relaxing serotonin- or norepinephrine-contracted aortic preparations. Although pinacidil was also a smooth muscle relaxant in the guinea pig trachea, guinea pig ileum, rat vas deferens, and rat stomach funds, the ED50 ranged from 1--25 μM in these smooth muscle preparations. In the trachea, pinacidil was most effective in relaxing histamine-induced contractions as compared to contractions induced by carbamylcholine. Thus, bronchodilatory effects of pinacidil might be most apparent when bronchoconstriction is produced by allergic responses that result from histamine release. Pinacidil was least effective in quiescent rat uterine smooth muscle, where approximately 80% of the maximum contractile response to oxytocin was maintained in the presence of 10−4 M pinacidil. Although a direct cardiostimulatory effect of hydralazine has been postulated, no direct stimulatory effect on guinea pig cardiac rate or force occurred with pinacidil. Furthermore, an inhibitory effect on rate and force of atrial responses occurred only in higher doses of pinacidil. The major metabolite of pinacidil, pinacidil-N-oxide, also relaxed the rat aorta, although it was approximately eight- to tenfold less potent than pinacidil. These data are consistent with the contention that pinacidil-N-oxide would contribute to the antihypertensive activity seen after pinacidil only when plasma levels were approximately tenfold greater than the parent compound. Furthermore, because of the relative insensitivity of other smooth and cardiac.

Injectable sustained release formulation

Abstract: A dairy cow injected with a sustained release formulation comprising bovine somatotropin, a wax, and an oil produces more milk for 28 days

Isolation and structural identification of nine avilamycins

Abstract: Avilamycin is an antibiotic complex produced by cultures of the organism Streptomyces viridochromogenes, strain NRRL 2860. These compounds belong to the orthosomycin family of antibiotics. Structural composition of the major avilamycins and several minor avilamycins are known. Nine additional minor avilamycins, designated F through N, have been isolated via semi-preparative silica gel or reverse-phase high performance liquid chromatography with final purification using a reverse-phase column loading solvent switching technique. 1H NMR and mass spectroscopy, negative ion fast atom bombardment (neg FAB) and electron impact, were used to structurally identify the avilamycins. All of the compounds were microbiologicallyactive and similar in structure to other known avilamycins.

Fluoxetine enantiomers as antagonists of p-chloroamphetamine effects in rats.

Abstract: The dextrorotatory enantiomer of fluoxetine was slightly more potent than the levorotatory enantiomer in antagonizing the depletion of brain serotonin by p-chloroamphetamine in rats. The time course of the depletion of brain serotonin at times out to 24 hr after the injection of p-chloroamphetamine was determined with or without simultaneous administration of one of the fluoxetine enantiomers. The dextrorotatory enantiomer prevented the depletion of brain serotonin at any time after p-chloroamphetamine. The levorotatory enantiomer prevented the initial depletion of brain serotonin at 2 and 4 hr, but by 8 hr brain serotonin concentration was decreased and by 24 hr the depletion of serotonin was almost as great as in rats treated with p-chloroamphetamine alone. The elevation of serum corticosterone that occurred acutely after injection of a low dose of p-chloroamphetamine was significantly antagonized by both enantiomers of fluoxetine, the dextrorotatory enantiomer being slightly more potent. In contrast, the lowering of DOPAC (3,4-dihydroxyphenylacetic acid) concentration in rat brain by p-chloroamphetamine was not antagonized by either enantiomer of fluoxetine, indicating this effect is not secondary to serotonin release by p-chloroamphetamine. The results are consistent with other evidence that both enantiomers of fluoxetine are potent inhibitors of serotonin uptake, the dextrorotatory enantiomer being longer-acting than the levorotatory enantiomer in rats.