Showing papers by "Eli Lilly and Company published in 1978"
TL;DR: There was a good correlation between calorimetric crystallinity and the (less precise) crystallinity derived from X-ray data, and provided amorphous and crystalline standards are appropriately chosen, the calorimal crystallinity correlates well with chemical stability.
261 citations
TL;DR: Substance P may have dual actions in brain, releasing endorphins at very low doses and directly exciting neuronal activity in nociceptive pathways at higher doses.
Abstract: Substance P produces analgesia when administered to mice in very small doses by the intraventricular route (125 to 5 nanograms per mouse) The analgesic effect can be blocked by naloxone At higher doses (greater than 50 nanograms per mouse), this activity is lost At these higher doses, however, substance P produced hyperalgesia when combined with naloxone and analgesia when combined with baclofen [beta-(4-chlorophenyl)-gamma-aminobutyric acid] Substance P may have dual actions in brain, releasing endorphins at very low doses and directly exciting neuronal activity in nociceptive pathways at higher doses
204 citations
TL;DR: The purpose of the present studies was to survey transmitter-receptor interactions in young, old and aged rats by monitoring norepinephrine-stimulated accumulation of cyclic nucleotides in slices of brain regions incubated in vitro.
132 citations
TL;DR: Rabbit peritoneal macrophages, when incubated in culture with bacterial lipopolysaccharides, release a factor which stimulates the production of collagenase and neutral proteases by chondro- cytes, and the possible role of these enzymes in cartilage destruction in chronic inflammatory conditions is discussed.
128 citations
TL;DR: The relative nucleofugicity of the nitro group in many aromatic nucleophilic substitution reactions rivals, and in some cases surpasses, that of the fluorine atom as discussed by the authors.
105 citations
TL;DR: The structure-activity relationships of some 1,3,4-trialkyl-4-phenylpiperidines are reported that clearly demonstrate the importance of a 3-methyl substituent in contributing narcotic antagonist properties within the phenyl-piperidine series as a whole.
Abstract: NARCOTIC antagonists are generally considered as N-methyl-cyclopropyl or N-allyl (for example, nalorphine) type derivatives of N-methyl (for example, morphine) agonists. This type of substitution has often been considered necessary for potent narcotic antagonist activity1,2. However, in the 4-phenylpiperidine series (as in meperidine) where a methyl substitution on the nitrogen has been associated with agonist activity, the substitution of an N-allyl derivative has not produced narcotic antagonists3–5. There are compounds, such as L-metazocine6,7 and profadol8, which contain a methyl-substituted basic nitrogen, and possess narcotic antagonist properties, but these are also agonists and their antagonist activity is relatively weak. During the pharmacological investigation of a new series of phenylpiperidines we discovered an N-methyl derivative that was a pure narcotic antagonist devoid of agonist effects. We also observed that nitrogen substituents that had increased agonist potency in the meperidine series9 when substituted in compounds of the present series surprisingly augmented antagonist potency to the level observed with naloxone4. Examination of the inhibition of specific 3H-naloxone binding of these derivatives in bovine striatal membranes demonstrated that their relative potency was due to differences in receptor interaction. We used the most potent member of the series to study its stereoselectivity. We report here the structure-activity relationships of some 1,3,4-trialkyl-4-phenylpiperidines that clearly demonstrate the importance of a 3-methyl substituent in contributing narcotic antagonist properties within the phenyl-piperidine series as a whole. These compounds may well represent the first new class of pure narcotic antagonists since the discovery of naloxone.
96 citations
TL;DR: Comparison of uptake inhibitors as antagonists of PCA is strongly influenced by the pharmacokinetics of the drugs involved.
95 citations
TL;DR: The results strongly suggest that somatostatin inhibits neuronal release of cholinergic and adrenergic transmitter substances in smooth muscle.
76 citations
TL;DR: Narasin is a new polyether antibiotic produced by a strain of Streptomyces aureofaciens that is effective in protecting chickens from coccidial infections and is active in vitro against gram-positive bacteria, anaerobic bacteria, and fungi.
Abstract: Narasin is a new polyether antibiotic produced by a strain of Streptomyces aureofaciens.It is purified by organic solvent extraction and silica gel chromatography. Narasin is active in vitro against gram-positive bacteria, anaerobic bacteria, and fungi and is effective in protecting chickens from coccidial infections.
61 citations
TL;DR: All of the results are compatible with the idea that 1-(m-trifluoromethylphenyl)-piperazine acts as a serotonin receptor agonist in rat brain.
58 citations
TL;DR: These experiments indicate that REM sleep is suppressed when 5-HT accumulates at synapses as a consequence of fluoxetine administration, and suggest that both NE and 5- HT can inhibit the cholinergic system that seems crucial for REM sleep.
TL;DR: This is the first in vitro cell migration model of inflammation in which gold compounds have demonstrated activity in micromolar concentrations, and it suggests a site of action for this antirheumatic drug, sodium aurothiomalate.
Abstract: N-formylmethionyl-leucyl-phenylalanine, a potent chemotactic peptide for human polymorphonuclear leukocytes, is less chemotactic for human blood monocytes. Esterification of the N-formylated tripeptide enhances its chemotactic activity for monocytes by more than 4 logs, whereas a decrease by 3 logs is observed for polymorphonuclear leukocytes. These results indicate the participation of the C-terminal carboxyl group in chemotaxis of different cell types. We have also observed the selective inhibition of chemotactic responsiveness of human blood monocytes by a clinically useful antirheumatic drug, sodium aurothiomalate. Since this is the first in vitro cell migration model of inflammation in which gold compounds have demonstrated activity in micromolar concentrations, it suggests a site of action for this antirheumatic drug.
Patent•
25 May 1978TL;DR: Antibiotic A54556, a complex of 8 individual factors, produced by submerged, aerobic fermentation of new Streptomyces hawaiiensis NRRL 15010, is active against Staphylococcus and Streptococcus which are penicillin resistant.
Abstract: Antibiotic A54556, a complex of 8 individual factors, produced by submerged, aerobic fermentation of new Streptomyces hawaiiensis NRRL 15010. The complex and the individual, separated factors are active against Staphylococcus and Streptococcus which are penicillin resistant.
Patent•
25 Oct 1978TL;DR: Amide derivatives of VLB, leurosidine and leurocristine are useful as anti viral and anti-neoplastic agents or as intermediates in the preparation of such agents as discussed by the authors.
Abstract: Amide derivatives of VLB, leurosidine, leurocristine and related dimeric alkaloids are useful as anti viral and anti-neoplastic agents or as intermediates in the preparation of such agents.
TL;DR: In fibroblasts from normal or familial hypercholesterolemic individuals, ML-236B caused a marked increase in reductase, and the incorporation of [2-14C]-acetate into sterol was decreased while the incorporation into fatty acids was increased.
TL;DR: Serotonin turnover, as measured by the rate of 5-hydroxyindoleacetic acid accumulation after probenecid administration, was decreased significantly still at 1 week after fenfluramine administration.
Abstract: SummaryFenfluramine and its N-demethyl metabolite, norfenfluramine (3-tri-fluoromethyl-amphetamine), lowered brain serotonin, 5-hydroxyindoleacetic acid, and tryptophan hydroxylase in rats acutely and the effect persisted for more than 1 week after a single ip dose of the drugs. Serotonin depletion by fenfluramine and norfenfluramine was blocked by pretreatment with fluoxetine, an inhibitor of uptake into serotonin neurons. Serotonin turnover, as measured by the rate of 5-hydroxyindoleacetic acid accumulation after probenecid administration, was decreased significantly still at 1 week after fenfluramine administration. The effects of fenfluramine and norfenfluramine on brain serotonin neurons in rats resemble those of p-chloroamphetamine and probably occur via similar mechanisms.
TL;DR: Dgradation rates for cefaclor in commercially prepared serum increased from 4- to 10-fold in comparison to rates obtained when samples were made in human serum freshly prepared in the authors' laboratory, Consequently, serum standards should be made in freshly prepared human serum.
Abstract: Cefaclor solutions in pH 2.5 and 4.5 buffers contained at least 90% of their initial activity after 72 h at 4°C. Samples in pH 6.0, 7.0, and 8.0 buffers contained 70, 46, and 34%, respectively, of their initial activity after 72 h at 4°C. After 72 h at 25°C, samples prepared with pH 2.5, 4.5, 6.0, 7.0, and 8.0 buffers contained 95, 69, 16, 5, and 3%, respectively, of their initial activity. After 72 h at 37°C, cefaclor solutions in pH 2.5 buffer contained 80% of the initial activity, whereas samples prepared in pH 4.5, 6.0, 7.0, and 8.0 buffers contained less than 20%. Laboratory-prepared plasma and serum samples showed an 8% loss in activity when incubated for 6 h at 4°C, a 51% loss when incubated for 6 h at 25°C, and a 48% loss when incubated for 2 h at 37°C. Clinical samples demonstrated a similar stability pattern. Degradation rates for cefaclor in commercially prepared serum increased from 4- to 10-fold in comparison to rates obtained when samples were made in human serum freshly prepared in our laboratory. Consequently, serum standards should be made in freshly prepared human serum.
TL;DR: The main criterion relied on to assess the pharmacological identity of the receptor populations acted upon by both families of agonists (the opiates and the endogenous peptides) in the production of analgesia has been the antagonism of both by naloxone.
Patent•
22 Jun 1978TL;DR: In this paper, a pharmaceutical preparation consisting of a taste-stable aqueous suspension of tall oil sitosterols is described, and a method for preparing such a suspension is provided.
Abstract: A pharmaceutical preparation is described which comprises a taste-stable aqueous suspension of tall oil sitosterols. A method is provided for preparing such a suspension.
Patent•
20 Oct 1978TL;DR: In this article, a film-forming formulation containing fluroandrenolide is presented, and the film can be removed by peeling or washing, depending on the type of the film.
Abstract: Film-forming formulation containing fluroandrenolide. The film can be removed by peeling or washing.
01 Jan 1978
TL;DR: The effect of quipazine was present in rats pretreated with 5,7-dihydroxytryptamine to destroy serotonin nerves and was not enhanced by fluoxetine pretreatment, compatible with the idea that quipazines increases serum corticosterone as a consequence of direct stimulation of serotonin receptors in brain.
Abstract: Quipazine, a serotonin receptor agonist, increased serum corticosterone within 30 min after its i.p. injection (at 10 mg/kg) into rats; the effect persisted at 1 and 2 hrs, but not at 4 hrs. Elevation of serum corticosterone did not occur with a 1.25 mg/kg dose of quipazine but was dose-related over a 2.5-20 mg/kg dose range. The effect of quipazine was completely prevented by methergoline, a serotonin receptor antagonist. The effect of quipazine was present in rats pretreated with 5,7-dihydroxytryptamine to destroy serotonin nerves and was not enhanced (as was the effect of L-5-hydroxytryptophan) by fluoxetine pretreatment. These data are compatible with the idea that quipazine increases serum corticosterone as a consequence of direct stimulation of serotonin receptors in brain.
TL;DR: After alpha adrenergic blockade in rat aorta, practolol and N-isopropylmethoxamine were equieffective as antagonists of relaxation to norepinephrine and isoproterenol although N- isopropolol was somewhat more effective than practiseolol.
TL;DR: Quantitation of the major components in cephalosporin C broths was done by a system involving separation by an ion-pair technique, and a method of equating uv potency of tylosin to microbiological potency is discussed.
Abstract: Procedures are described for the analysis of cephalosporin C or tylosin in fermentation broths by high performance liquid chromatography (HPLC). Quantitation of the major components in cephalosporin C broths was done by a system involving separation by an ion-pair technique. Tylosin data were obtained using a reverse phase method. A method of equating uv potency of tylosin to microbiological potency is discussed. A comparison of HPLC with a microbiological method for the determination of tylosin concentration is also made.
Patent•
22 Sep 1978TL;DR: In this article, an implant which has an inert, biocompatible core with a coating comprising from about 5 to about 40% of estradiol in a bi-compatible dimethylpolysiloxane rubber was described.
Abstract: There is disclosed an implant which has an inert, biocompatible core with a coating comprising from about 5 to about 40% of estradiol in a biocompatible dimethylpolysiloxane rubber. When the implant is placed under the skin of a ruminant animal the estradiol is released at a substantially constant rate to produce a greater than normal weight gain in the animal. The implant remains intact and may be removed from the animal at the end of the desired period of drug administration.
TL;DR: In this article, a comparison of chloroamphetamine and various analogs influence brain serotonin neurons through multiple actions, including short-term and long-term depletion of serotonin and among inhibition of tryptophan hydroxylation, release of serotonin, inhibition of serotonin reuptake, and inhibition of monoamine oxidase.
Abstract: p-Chloroamphetamine and various analogs influence brain serotonin neurons through multiple actions. Comparison of these compounds has permitted the distinction between short-term and long-term depletion of serotonin and among inhibition of tryptophan hydroxylation, release of serotonin, inhibition of serotonin reuptake, and inhibition of monoamine oxidase as mechanisms involved in the actions of these agents on serotonin neurons.
TL;DR: The two major groups of serotonin neurotoxins currently known are the halogenated amphetamine derivatives, the most extensively studied being p-chloroamphetamine, and the hydroxy derivatives of serotonin, particularly 5,6and 5,7-dihydroxytryptamines.
Abstract: The two major groups of serotonin neurotoxins currently known are the halogenated amphetamine derivatives, the most extensively studied being p-chloroamphetamine, and the hydroxy derivatives of serotonin, particularly 5,6and 5,7-dihydroxytryptamines. Destruction of serotonin neurons by either type of agent results in neurochemical changes in all parameters specifically associated with brain serotonin neurons, namely, decreases in tryptophan hydroxylase, in serotonin and 5-hydroxyindoleacetic acid content, and in the high-affinity uptake of serotonin. The neurochemical effects of these two groups of serotonin neurotoxins can be compared briefly as follows. Time Course of the Neurochemical Eflects. Serotonin depletion occurs rapidly with halogenated amphetamines and dihydroxytryptamines. The halogenated amphetamines apparently have two separate actions on the serotonin neuron: an immediate effect, whereby inhibition of serotonin synthesis and release of bound serotonin rapidly deplete serotonin content, and the prolonged neurotoxic effect. Halogenated amphetamines competitively inhibit serotonin uptake shortly after they are given and rapidly lead to inhibition of tryptophan hydroxylase, but these effects and the depletion of 5-hydroxyindoles are not irreversible at first; that is, the halogenated amphetamines are not immediately neurotoxic.', In contrast, the hydroxytryptamines probably exert neurotoxic effects on the serotonin neurons more rapidly; at least there has been no evidence that their effects can be reversed. The neurochemical manifestation of the neurotoxic effect depends partly on the turnover of tryptophan hydroxylase and on the uptake system. Though the halogenated amphetamines act at least as rapidly to deplete serotonin content, the dihydroxytryptamines are more rapidly neurotoxic. Reversibility. As discussed above, the effects of the halogenated amphetamines are initially reversible. The effects of p-chloroamphetamine,? p-bromoamphetamine,% and fenfluramine become partially irreversible within 6-8 hr and totally irreversible within 32-48 hr. The effects of the dihydroxytryptamines are apparently never reversible. Route of Administration. The dihydroxytryptamines do not cross the blood-brain barrier and therefore must be injected intraventricularly, intracisternally, or otherwise directly into the central nervous system. The halogenated amphetamines, in contrast, cross the blood-brain barrier readily. In fact, the neurochemical effects of pchloroamphetamine are more pronounced when it is given systemically than when it is given intraventricularly, apparently because in the latter case, it leaks out of the brain so rapidly. p-chloroamphetamine is approximately as potent a serotonin neurotoxin on a milligram per kilogram dose basis when given intraperitoneally as when given intraventricu-
Patent•
20 Apr 1978TL;DR: Derivatives of 4-desacetyl VLB C-3 carboxhydrazide are useful as intermediates for active anti-tumor conjugates as mentioned in this paper, but they are not suitable for use in medical applications.
Abstract: Derivatives of 4-desacetyl VLB C-3 carboxhydrazide, active anti-tumor agents and useful as intermediates for active anti-tumor conjugates.
TL;DR: The rigid structure of LR5182 suggested a gauche conformation of dopamine to be favored by the striatal uptake of dopamine in rat striatal synaptosomes.
Patent•
31 Mar 1978TL;DR: In the presence of boron tribromide, trifluoride or stannic chloride, 4-(1-hydroxy)-1-methylethyl)-3-cyclohexen-1-one with a 5-substituted resorcinol was shown to yield either a 2,7-dihydroxy-5-isopropylidene-9-substantituted 2,6-dimethyl or a 6-hexahydro-9H-dibenzo[b,d
Abstract: Reaction of 4-(1-hydroxy-1-methylethyl)-3-cyclohexen-1-one with a 5-substituted resorcinol in the presence of boron tribromide, boron trifluoride or stannic chloride provides, depending upon the duration of reaction, either a 2,7-dihydroxy-5-isopropylidene-9-substituted-2,6-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin or a 6a,10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.