Showing papers by "Eli Lilly and Company published in 1981"

Antiestrogenic and antiandrugenic benzothiophenes

Abstract: 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, its ethers and esters, and the physiologically acceptable acid addition salts thereof, are valuable antiestrogens and antiendrogens

Magnetically-localizable, biodegradable lipid microspheres

Abstract: A drug carrier formulation consisting of magnetically-localizable, biodegradable lipid microspheres containing a magnetically-responsive substance, one or more diodegradable lipids and one or more nontoxic surfactants is described herein. There is also described a process for preparing such microspheres wherein the magnetically-responsive substance is wetted with surfactant and part of the lipids, then this material is added to the remaining lipids and heated to 90-100°C., water is added, the mixture is sonicated to obtain a microemulsion, which is then cooled and lyophilized to obtain the product.

Synthesis of acylated benzothiophenes

Abstract: A group of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]benzo[b]thiophenes are prepared by acylation of a methyl-protected starting compound followed by demethylation in a single reaction mixture.

Isolation of three separate anaphylatoxins from complement-activated human serum

Abstract: Recent methodologies used in preparing anaphylatoxins from complement-activated serum are described. Activation of the alternative pathway generates C3a and C5a; however, activation of the classical pathway is required to generate the anaphylatoxin from C4. This article describes an activation scheme that simultaneously generates all three of the anaphylatoxins (e.g., C3a, C4a and C5a) in human serum and outlines a procedure for isolating each as homogeneous products. Purification of intact anaphylatoxins directly from complement-activated serum takes place only if an exopeptidase in serum, known as carboxypeptidase N (SCPN), is properly inhibited. A new series of mercapto derivatives of arginine analogs are introduced as potent and effective inhibitors of SCPN. These inhibitors permit normal complement activation but prevent degradation of the released activation fragments C3a, C4a or C5a.

Metkephamid, a systemically active analog of methionine enkephalin with potent opioid alpha-receptor activity.

Abstract: Metkephamid is an analog of methionine enkephalin that retains high affinity for the delta receptor and is a systemically active analgesic. Since it is at least 100 times more potent than morphine as an analgesic when placed directly into the lateral ventricles, and is 30 to 100 times more potent on the delta receptor and yet is roughly equipotent on the mu receptor in vitro, it is concluded that it probably produces analgesia by action on delta receptors as well as, or rather than, on mu receptors. It has less tendency to produce respiratory depression, tolerance, and physical dependence than standard analgesics, and it is presently undergoing clinical trial.

Properties of Streptomyces fradiae Mutants Blocked in Biosynthesis of the Macrolide Antibiotic Tylosin

Abstract: We isolated numerous mutants of Streptomyces fradiae blocked in tylosin biosynthesis after N -methyl- N′ -nitro- N -nitrosoguanidine mutagenesis. These mutants were classified into nine groups, based upon the tylosin-like compounds produced and upon cofermentation analyses. More than 80% of the mutants isolated produced no tylosin-like compounds, and the majority of these were blocked only in the formation of tylactone. Four classes of mutants blocked in the biosynthesis or addition of tylosin sugars were isolated; tylA mutants were blocked in the formation of all three tylosin sugars, whereas tylB, tylC , and tylD mutants were blocked specifically in the biosynthesis or the addition of mycaminose, mycarose, and 6-deoxy-d-allose, respectively. Two classes of mutants ( tylH and tylI ) blocked in specific oxidations of tylactone and two classes ( tylE and tylF ) blocked in specific O-methylations of demethylmacrocin and macrocin were also characterized. Cofermentation and bioconversion studies with these mutants suggested the following relationships: (i) the tylosin sugars are derived from a common intermediate; (ii) tylactone is the first intermediate which can be excreted in appreciable quantities; (iii) the addition of mycaminose to the C-5 hydroxyl group of tylactone must precede oxidations at C-20 and C-23; (iv) oxidation at C-20 normally precedes the attachment of mycarose to the 4′ hydroxyl position of mycaminose; and (v) 6-deoxy-d-allose is added to the C-23 hydroxyl position of the lactone and subsequently O-methylated at 2‴ and 3‴ positions. The O-methylations appear to be the final two steps in tylosin biosynthesis, and the 2‴ O-methylation must occur before the 3‴ O-methylation can take place. All of the tyl mutants except the tylG mutants produced relatively high levels of tylosin-like intermediates or shunt products. Mutants blocked in specific steps other than 3‴ O-methylation, including a mutant blocked in 2‴ O-methylation of demethylmacrocin, produced normal levels of macrocin O -methyltransferase. Mutants apparently containing specific tylosin structural gene mutations produced normal levels of aerial mycelia and spores, produced low levels of tylosin aldehyde reductase, and were resistant to high levels of tylosin. However, three atypical tylG mutants produced no tylosin-like compounds, could not cosynthesize tylosin with any other tyl mutant, could not bioconvert tylactone or macrocin to tylosin, and produced no macrocin O -methyltransferase. These three mutants produced elevated levels of tylosin aldehyde reductase. In addition, one was very succeptible to tylosin and did not produce aerial mycelia or spores.

Evidence for biological action of the antiestrogens ly117018 and tamoxifen by different mechanisms

Abstract: The influence of LY117018 and tamoxifen on established uterotropic influence of estradiol was examined in immature ovariectomized rats. When LY117018 was introduced on the fourth day of estradiol treatment, it regressed the uterotropic effect of estradiol. However, tamoxifen did not attenuate estradiol activity under these conditions. Injection of estradiol, commencing on the fourth day of LY117018 treatment, elicited no increase in uterine weight, while tamoxifen caused substantial uterotropic action in the presence of established, continuous LY117018 treatment. The uterotropic influence of tamoxifen also occurred when it was administered concomitantly with LY117018, and a similar result was observed following the injection of 4-hydroxytamoxifen with LY117018. These observations demonstrate that LY117018 can block or regress uterotropic effects of estradiol, but it cannot antagonize the action of tamoxifen or its hydroxylated metabolite. This suggests that these antiestrogens might act at separate sites or by different molecular mechanisms.

Elevation of Serum Corticosterone Concentrations in Rats by Pergolide and Other Dopamine Agonists

Abstract: Pergolide, a dopamine agonist, elevated serum corticosterone concentrations in rats. The elevation was dose dependent, a maximum effect being produced at a dose of 0.3 mg/kg, ip. The serum corticosterone concentration was highest 30–60 min after pergolide injection and had returned to normal by 4 h. Spiperone and haloperidol, known dopamine antagonists, blocked the increase in serum corticosterone. Metergoline and mianserin did not alter the increase in serum corticosterone caused by pergolide, but these serotonin antagonists prevented the increase caused by quipazine, a serotonin agonist. Haloperidol did not influence serum corticosterone elevation by quipazine, but spiperone partially antagonized quipazine's effect atdoses higher than those required to prevent the effect of pergolide (spiperone is known to block some serotonin receptors as well as dopamine receptors). The ED 50 for spiperone in antagonizing serum corticosterone elevation by pergolide was 0.003– 0.01 mg/kg whereas the EDr,o for spiperone...

Sustained release capsule for ruminants

Abstract: A sustained release capsule for introduction through the esophagus to the rumen of a ruminant has a tubular barrel containing a body of active composition urged by a piston and spring into sealing engagement with a constriction end wall shaped with a peripheral curved border leading to a frustoconical portion defining a delivery opening, the shape and width of such wall controlling the release rate to the rumen. The open front end of the barrel is closed by a hemispherical cap connected at the center of its convex outer face to a wing having opposite arms normally outstanding at near 90° from the capsule body but resiliently bendable over a long arc along the convex face of the cap to retracted positions for introduction of the capsule through the esophagus. In the rumen, the arms return to near 90° positions to hinder regurgitation of the capsule and to better withstand working and contractions of the rumen.

Physiologic disposition of pergolide

Abstract: Pergolide, a synthetic ergoline, is a potent long-acting dopaminergic drug effective in Parkinson's disease and amenorrhea-galactorrhea. After 138 μg l4C-pergolide orally to healthy subjects, radioactivity was present in plasma and red blood cells. Salivary radioactivity was one third to one tenth that in plasma. Radioactivity in plasma appeared after 15 to 30 min, peaked at 1 to 2 hr, and was barely detectable after 96 hr. Plasma radioactivity was not attributable to pergolide, and the levels did not correlate well with the duration of the prolactin-lowering effect induced by pergolide. Pergolide became bound to several plasma proteins and could not be displaced by other drugs that are also bound or by possible metabolites of pergolide. Radioactivity was eliminated as pergolide metabolites in urine (55%), feces (40%), and breath (5%, as 14CO2). Clinical Pharmacology and Therapeutics (1981) 30, 258–265; doi:10.1038/clpt.1981.157

3-Aryloxy-3-phenylpropylamines

Abstract: The (-)-enantiomer of the compound of formula (I): and its pharmaceutically-acceptable salts, are effective antidepressant agents.

Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purkinje cell degeneration in pcd mutant mice.

Abstract: The Purkinje cell degeneration mutant (pcd) is characterized by a complete loss of cerebellar Purkinje cells. Norepinephrine causes an accumulation of cyclic AMP in the cerebellum of pcd that is far greater than in normal mice. Experiments were conducted 1) to correlated changes in the cyclic-nucleotide response with a histologic examination of the cerebellum during neuronal loss and 2) to examine the role of cyclic AMP catabolism and adenosine receptor interactions in the phenomenon. The greatest elevation in cyclic AMP occurred between 30 and 128 days of age when a severe astrocytic response was demonstrated throughout the cerebellar cortex. Purkinje cells had degenerated by 45 days of age. Norepinephrine elicited a smaller increase in cyclic AMP from 155-day-old mice than at earlier ages, and the response continued to decrease with age; at 270 days, equal accumulation, and at 365 days. lower accumulation of cyclic AMP was detected in pcd cerebella. During this time, the Purkinje cell debris had been removed, the granule cell layer was depleted of granule cells, and the molecular layer was deprived of a large number of parallel fibers. However, although phagocytosis of neuronal debris was completed, large numbers of astrocytic processes were still seen in the neuropil. Biochemical experiments in vitro established that the exaggerated accumulation of cyclic AMP in the presence of norepinephrine was not due to lower catabolism of cyclic AMP, a synergistic interaction with adenosine, or a result of lower protein in the pcd cerebellum. The correlates of heightened norepinephrine-stimulated accumulation of cyclic AMP with neuronal loss and the glial cell reaction might indicate that cyclic nucleotides play a role in controlling some glial cell functions, ie, proliferation, migration, and phagocytosis.

Airborne particle dispenser

Abstract: An airborne apparatus for dispensing particulate agricultural materials in precise dosages includes a rotor to uniformly deliver the particulate material from a container carried by the aircraft to a dispensing opening. A blade is provided adjacent the periphery of the rotor. The blade and the periphery of the rotor cooperate to reduce the interference of particulate material with operation of the rotor. A multi-part rotor housing provides adjustability for a variety of particulate materials. Such housing includes an arcuate housing portion and a gate-forming housing portion. The gate-forming housing portion and arcuate housing portion may be hinged to the remainder of the housing and form a dispensing opening. The arcuate housing portion can be adjusted with respect to the periphery of the rotor and can provide a reservoir of adjustable capacity between the dispensing opening and the rotor periphery. The gate housing portion is held in its normal position against the arcuate housing portion to close the dispensing opening but is movable to a position in which the dispensing opening is open.

Process for producing an insulin

Abstract: Production of insulin or an insulin analog is provided by combination of an A-chain and a B-chain, which comprises bringing the S-sulfonated form of the A-chain, the S-sulfonated form of the B-chain, and a thiol reducing agent together in an aqueous medium under conditions which produce a mixture having (1) a pH of from about 8 to about 12, (2) a total protein concentration of from about 0.1 to about 50 milligrams per milliliter, and (3) an amount of thiol reducing agent which affords a total of from about 0.4 to about 2.5 --SH groups per each --SSO 3 - group present in the total amount of A- and B-chain S-sulfonates, and allowing formation of insulin or an insulin analog to occur by maintaining the mixture at a temperature of from about 0° C. to about 25° C. and in an environment which provides a source of oxygen.

Sensitive-skin care regime

Abstract: A method of decreasing the sensitivity of the skin without causing irritation is described, using a four component cosmetic regime. The four components comprising the regime are: a cleanser, a toner, a moisturizer, and a cream.

Process for producing an insulin precursor

Abstract: A proinsulin-like disulfide insulin precursor is produced from its corresponding linear chain S-sulfonate insulin precursor by reacting the S-sulfonate with a mercaptan in an amount which provides from about 1 to about 5 --SH moieties per --SSO3 - moiety in an aqueous medium at a pH of from about 7 to about 11.5 and at an S-sulfonate concentration of up to about 10 mg. per ml. of aqueous medium.

Parental Development of Eimerian Coccidia in Sandhill and Whopping Cranes1

Abstract: In contrast with isosporoid species of coccidia that have established extraintestinal phases of development, the eimeriids, except for a few species, generally have been considered inhabitants of the intestinal tract. Eimeria infection in sandhill cranes (Grus canadensis) and whooping cranes (G. americana) may result in disseminated visceral coccidiosis. Nodules were observed in the oral cavity of 33% (n = 95) of the G. canadensis at the Patuxent Wildlife Research Center (PWRC) in Laurel, MD. Necropsy of six of the afflicted cranes revealed granulomatous nodules in many tissues and organs. Histologic studies disclosed protozoan organisms morphologically resembling schizonts in the granulomas, and endogenous stages of coccidia were present in the intestines of four birds. Fecalysis of three of four sandhill cranes yielded oocysts of E. reichenowi and E. gruis. Only E. reichenowi-type oocysts were recovered from a dead whooping crane sample. Domestic broiler chicks each intubated with about 1 times 106 pooled sporulated oocysts of E. reichenowi and E. gruis were not infected. Exposure of six incubator-hatched and hand-reared sandhill crane chicks to oocysts artificially (two chicks) and naturally (four chicks) resulted in typical infection of intestinal epithelium with invasion of subepithelial tissues extending to the muscular layer and widespread extraintestinal development. Asexual and sexual stages occurred primarily in macrophages in the liver, spleen, heart, and lung. In the lung, oocysts were found in bronchial exudate and epithelial lining cells. Six of ten G. canadensis chicks, one adult G. americana, and three of five G. americana chicks that died naturally at PWRC had disseminated visceral coccidiosis.

N-arylbenzamide derivatives

Abstract: N-arylbenzamide derivatives of formula (I) wherein Z is oxygen or sulfur, R 1 ,R 2 , R 3 are hydrogen or a substituent, R 4 is an heteroaryl group linked to the nitrogen atom by a carbon atom, selected from possibly substituted isoxazole, isothiazole, pyrazole, imidazole, thiadiazole, oxadiazole or pyridazine. These compounds can be used as herbicides.

Benzamides, compositions and agricultural method

Abstract: N-Aryl benzamides wherein the aryl group is a nitrogen containing heterocycle are useful as selective herbicidal agents. Compositions containing the novel benzamides and a herbicidal method of selective weed control are disclosed.

Determination of moxalactam in human body fluids by liquid chromatographic and microbiological methods.

Abstract: High-performance liquid chromatographic methods for determination of the isomers of moxalactam in plasma and urine have been developed. Conventional reverse-phase chromatography was used for plasma assays, and an ion-pairing reagent was included for urine assays. Detection limits were 1.5 micrograms/ml of plasma and 7.5 micrograms/ml of urine. The high-performance liquid chromatographic assays were extensively compared with a microbiological assay (detection limit, 1 microgram/ml), using samples from human volunteers to whom moxalactam had been administered as well as plasma and urine from untreated humans, to which moxalactam was added. The correlations between the assays were quite good, but the precision and accuracy of the high-performance liquid chromatographic methods were superior. Both types of assays were used in a study of the stability of moxalactam-containing samples at various temperatures.

Role of serotonin in the hypothalamic regulation of pituitary function.

Abstract: One function of serotonin neurons in brain appears to be control of pituitary hormone secretion. The anterior lobe of the pituitary gland secretes adrenocorticotropic hormone (ACTH), prolactin, growth hormone, thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH); the secretion of these hormones is governed by releasing factors and in some cases by release-inhibiting factors from the hypothalamus. Regulation of the secretion of these factors apparently involves complex neural circuitry, but serotonin neurons seem to represent one link in the control mechanisms for most if not all of these pituitary hormones. We will review briefly some of the more recent pharmacologic evidence supporting such a role of serotonin neurons, focusing primarily on ACTH and prolactin, the two hormones of major interest in our laboratories.

Method for stabilizing and selecting recombinant dna containing host cells

Abstract: The present invention is an improvement in the method for stabilizing and selecting host cells containing recombinant DNA. The method involves transforming a host cell with a recombinant DNA cloning vector which contains the ˜2.5 kb BglII cI repressor gene-containing restriction fragment of bacteriophage λ and then lysogenizing the transformed host cell with a lysogenic organism which contains a marker which is lethal or conditionally lethal in the host cell but which is repressed in the transformed host cell by the repressor gene contained in the recombinant DNA cloning vector. The vector additionally contains a gene which codes for the expression of human proinsulin. The invention further comprises related recombinant DNA cloning vectors, transformed host cells and lysogenized transformed host cells.