bluuebunny/crossref_metadata_2025_split huggingface dataset:
Status of safety pharmacology in the pharmaceutical industry, 1993
Authors: Kinter Lewis B. , Gossett Kent A. , Kerns William D. 
Published: January 2005

AbstractGeneral pharmacology and safety pharmacology studies are of considerable value in drug discovery and safety assessment. The knowledge gained from these studies adds mechanistic perspectives and functional dimensions to contemporary animal pharmacology and toxicology studies. If conducted prior to initiation of drug development activities, general pharmacology and safety pharmacology studies can assist in the selection of drug classes and specific candidates for drug development, and contribute to selection of rational high doses for chronic toxicity studies. If conducted prior to initiation of clinical safety studies, these studies can influence the design of clinical protocols so that appropriate strategies are put in place to ensure appropriate patient management and care. Finally, general pharmacology and safety pharmacology studies can provide an important communication pathway between the non‐clinical and clinical segments of a drug development program.
Estimating protein function from combinatorial sequence data using decision algorithms and neural networks
Authors: Goldman Ellen R. , Füllen Georg , Youvan Douglas C. 
Published: January 2005

AbstractCorrelations between protein sequences and phenotypes were explored using databases of combinatorial cassette mutants of pigment‐protein complexes. Heuristically formulated decision algorithms and computer implemented neural networks were compared to determine their accuracy in classification of phenotypic categories. For the databases examined, decision algorithms employing very simple rules were able to properly classify mutants 80–84% of the time, based only on the amino acid sequence of the mutagenized region. Such decision algorithms did not require the formulation of any rules that involved site‐to‐site interactions, but rather, performed well based on the stringency of specific critical sites in the protein that accept only a restricted set of amino acids. In some cases, neural networks scored almost 10% higher than decision algorithms on the same databases (i.e., 94%). However, the success of the primitive decision algorithms and perceptrons at sorting sequences into categories suggests that linear effects predominate in the classification of a mutant's phenotype. Such methods should be generally applicable to the broad spectrum of databases that are currently being generated in combinatorial chemistry and biology experiments. © 1994 Wiley‐Less, Inc.
Ca2+ channel toxins: Tools to study channel structure and function
Authors: Saccomano Nicholas A. , Ahlijanian Michael K. 
Published: January 2005

AbstractA remarkable diversity of voltage‐dependent Ca2+ channels exists in the mammalian nervous system to subserve the broad and complicated roles that impulse‐generated changes in intracellular Ca2+ play in neuronal functions such as synaptic transmission, cell firing, gene expression, and related functional sequelae. A detailed understanding of how such temporally and subcellularly restricted changes in intracellular Ca2+ affect cellular and synaptic function requires selective pharmacological tools that can specifically dissect one channel apart from the operating neuron or neuronal system. A set of selective reagents currently available to the Ca2+ channel pharmacologist or physiologist has been provided by a variety of predatory animals from disparate phylogenetic origins. It is fortunate that these creatures invested in countless years of toxin engineering providing essential implements which otherwise might have been obtained only through an enormous effort on the part of current‐day scientists. This review will offer a discussion of the current understanding of the pharmacology and chemistry of important Ca2+ channel toxins in the context of the growing field of neuronal Ca2+ channel structure and function. © 1994 Wiley‐Liss, Inc.
Lifibrol increases hepatic cholesterol 7α‐hydroxylase activity in sprague‐dawley rats
Authors: Dinh Dac M. , Michael Funk G. , Vidmar Thomas J. , Spilman Charles H. 
Published: January 2005

AbstractThe hypocholesterolemic drug lifibrol was administered orally to Sprague‐Dawley rats to determine its effects on lipoprotein cholesterol distribution and hepatic HMG‐CoA reductase and cholesterol 7α‐hydroxylase activities. The effects of lifibrol on those endpoints were compared with the effects of gemfibrozil and lovastatin. When administered to either chow‐fed or cholesterol‐fed rats, lifibrol (25 or 50 mg/kg/day) caused a redistribution of lipoprotein cholesterol such that HDL increased and VLDL + LDL decreased significantly. Gemfibrozil (30 or 50 mg/kg/day) caused similar changes in lipoprotein cholesterol distribution. In contrast, lovastatin (10 mg/kg/day) decreased both HDL and VLDL + LDL in chow‐fed animals, but had no effect in cholesterol‐fed animals. Hepatic HMG‐CoA reductase activity was increased in rats treated with lifibrol (50 mg/kg/day), gemfibrozil (50 mg/kg/day), and lovastatin (10 mg/kg/day). The most significant finding is that lifibrol was the only drug that increased hepatic cholesterol 7α‐hydroxylase activity. This observation in rats separates the mechanism of action of lifibrol from those of the HMG‐CoA reductase inhibitors and the fibrates, and suggests that one mechanism of action of lifibrol is to enhance cholesterol elimination through conversion to bile acids. © 1994 Wiley‐Liss, Inc.
Expression and characerization of human kainate receptor subunits in Escherichia coli and mammalian cells
Authors: Foldes Robert L. , Fantaske Robert P. , Korczak Bozena , Hoo Ken H. , Nutt Stephen L. , Kamboj Rajender K. 
Published: January 2005

AbstractCellular expression systems for human kainate receptor subunits (EAA1 and EAA2) have been developed as tools to support drug screening and rational drug design. EAA1 and EAA2 sequence‐specific polyclonal antibodies were generated to characterize polypeptide expression on introduction of appropriate plasmid expression constructs to Escherichia coli (E. Coli), chinese hamster ovary (CHO) and human embryonic kidney (HEK‐293) cells. A polypeptide with an apparent molecular mass of ∼ 120 kilodaltons (kDa) was identified by Western blot analysis in CHO and HEK‐293 cells expressing EAA2. Three major immunoreactive bands of 116, 110, and 90 kDa were identified in HEK‐293 cells expressing EAA1. The polyclonal antibodies will allow the direct determination of EAA1 and EAA2 expression in human brain. Pharmacological characterization of a stable CHO cell line expressing EAA2 revealed a dissociation constant for kainate (KD) of 1.92 ± 0.28 nM (n = 3). This is the first report describing a stable cell line expressing EAA2 and the third report describing a stable cell line expressing a human glutamate receptor subunit. These studies are an important prelude to discovery of EAA1 and/or EAA2 specific drugs. © 1995 Wiley‐Liss, Inc.
Pharmacological antagonism of α‐adrenergic agonist induced increases in canine intraurethral pressure in vivo
Authors: Brune Michael E. , Buckner Steven A. , Polakowski James , Kerwin James F. , Hancock Arthur A. 
Published: January 2005

AbstractTreatment with α1 antagonists represents a pharmacological alternative to surgery for the treatment of urinary obstruction associated with benign prostatic hyperplasia (BPH). A minimally invasive method to measure elevation of prostatic urethral tone through a urethral catheter was used to study the effects of α‐adrenoceptor agonists and antagonists on canine intraurethral pressure (IUP). α1‐adrenoceptor agonists, but not α2 agonists, elicited elevations in IUP. The contractile response was primarily the result of prostatic smooth muscle contraction, since it was of smaller magnitude in female dogs or in male dogs outside of the prostatic urethra. The contractile responses to epinephrine obtained in the absence of antagonist on the same or different test dates were highly reproducible in dogs greater than 2 years of age. The increase in IUP caused by epinephrine was specifically antagonized by α1‐adrenoceptor antagonists, in direct proportion to their potency in isolated canine prostatic strips in vitro and in proportion to their affinity at receptors determined in radioligand binding assays in vitro. These data confirm the role of α1‐adrenoceptors in canine prostatic smooth muscle contraction and this relatively non‐invasive in vivo model will allow the study of novel compounds for their effects on canine prostatic tone. © 1995 Wiley‐Liss, Inc.
Intranasal delivery of human growth hormone: Optimization of formulation
Authors: Albertsson‐Wikland Kerstin , Hedin Lars , Jansson Peter , Rosberg Sten , Wikström Conny 
Published: January 2005

AbstractTen different formulations of recombinant human growth hormone (hGH) and a permeation enhancer of the nasal mucosa, sodium tauro‐24,25‐dihydrofusidate (STDHF) were administered intranasally (i.n.) to ten patients with classical GH deficiency. The formulations contained three variables: the hGH content (2, 4.1, or 6.3 mg = 4, 8.25, or 12.5 IU), the concentration of STDHF (0.75, 1, or 1.25%) and the spray volume (2 × 35, 2 × 53, or 2 × 70 m̈l). The influence of these variables on the bioavailability of hGH after i.n. administration and the local (nasal) irritation were assessed. The bioavailability was measured as the plasma concentration of hGH obtained by blood sampling, prior to and at frequent intervals for up to 5 h after administration. The effects on the nasal mucosa were evaluated by nasal inspections before and after each administration and also by using a self‐rating protocol to estimate the nasal sensations for each dose. The influences of the three variables (hGH content, STDHF concentration, and spray volume) on the bioavailability of hGH were analyzed by analysis of variance and multivariate statistical analysis being a useful way to evaluate multiple factors in pharmaceutical preparations with a limited number of observations in early clinical trials. This study demonstrates that formulations with low spray volumes (2 × 35 m̈l) resulted in a lower uptake of hGH and somewhat less inter‐individual variability compared to larger volumes (2 × 53, 2 × 70 m̈l) and that the concentrations of STDHF (0.75, 1, or 1.25%) had no significant effect on the bioavailability. The higher concentrations of STDHF were accompanied by more intense nasal sensations even if none of the formulations resulted in any damage of the nasal mucosa as determined by nasal inspections.
OHM3597: A novel fentanyl derivative with morphine‐like behavioral effects in rhesus monkeys
Authors: France Charles P. , Carr Daniel J. J. , Brockunier Linda L. , Bagley Jerome R. 
Published: January 2005

AbstractOHM3597, a fentanyl‐like piperidine with a thalidomide‐like moiety, was studied in rhesus monkeys for its behavioral effects and for its effects on lipopolysaccharide (LPS)‐induced production of tumor necrosis factor (TNF)‐α, OHM3597 had morphine‐like discriminative stimulus effects that were antagonized by naltrexone in a manner that was consistent with μ receptor mediation. OHM3597 also had antinociceptive effects, producing a maximal (20 sec) antinociceptive effect in a tail withdrawal procedure with a 50°C stimulus. This effect of OHM3597 also was antagonized by naltrexone in a dose‐related manner. Behavioral effects of this fentanyl derivative had a rapid onset and a relatively short duration of action; discriminative stimulus effects were evident 3 min after subcutaneous (sc) administration of 0.32 mg (0.58 μM)/kg of OHM3597 and the duration of antinociceptive effects produced by 1.0 mg (1.6 μM)/kg (sc) was less than 90 min. OHM3597 also was compared to thalidomide for its effects on LPS‐induced TNF‐α production in peripheral blood mononuclear cells that were obtained from drug‐naive rhesus monkeys. Thalidomide suppressed the production of TNF‐α in a concentration‐dependent manner with concentrations of 10 nM and 1 μM of thalidomide decreasing TNF‐α levels to 81 and 65%, respectively, of control (saline) values. In contrast, up to a concentration of 1 μM, OHM3597 failed to suppress LPS‐induced TNF‐α production. These results demonstrate OHM3597 to be a potent, morphine‐like opioid with a relatively short duration of action. Although OHM3597 did not alter TNF‐α production, a compound with both antinociceptive and immunomodulatory effects might be available within this chemical series and could provide a unique approach to the concurrent treatment of pain and infectious disease. © 1995 Wiley‐Liss, Inc.
Facilitating effects of SR 57746A on short‐term memory in an operant delayed alternation task in aged rats
Authors: Roux Sylvain , Hubert Isabelle , Wettstein Joseph G. , Soubrié Philippe , Le Fur Gérard , Porsolt Roger D. 
Published: January 2005

AbstractThe effects of SR 57746A during acquisition and on stabilized performance of a delayed alternation task in a Skinner Box (Model E 10.10, Coulbourn Instruments, Lehigh Valley, PA) were investigated in aged rats (22–26 months old). Test sessions consisted of repeated trials during which animals were first presented with a single lever (left or right) followed several seconds later by two levers. A press on the lever opposite to that presented previously (delayed alternation) was rewarded. The number of correct responses and the reaction times to the one‐ and two‐lever presentations were recorded. SR 57746A (0.3 and 3 mg/kg p.o.) was first evaluated during the acquisition of the delayed alternation, given before each of 10 daily acquisition sessions to different groups of aged animals. The imposed delay was 5 sec. Afterward, training continued without drug until asymptotic performance was reached. Rats were then given repeated drug test sessions during which different intervals (5, 10, and 20 sec) were presented in a random order. During this phase, both young and aged animals received all the different treatments (SR 57746A at 0.3, 1, and 3 mg/kg and vehicle p.o.). Aged animals showed clear deficits during both acquisition and stabilized performance phases. SR 57746A, particularly at the highest dose tested (3 mg/kg p.o.), clearly increased response accuracy of aged animals both during acquisition of the delayed alternation and during stabilized performance. In the latter phase, the facilitation of response accuracy was observed only in conditions (10 sec retention delay) where aged animals showed a deficit compared with young animals. SR 57746A did not affect response accuracy during stabilized performance in young animals at any delay. The drug‐induced increase in response accuracy in aged animals occurred at a dose of SR 57746A (3 mg/kg p.o.) that lengthened reaction times, particularly simple reaction times, during both acquisition and stabilized performance and also lengthened reaction times in young animals during the stabilized performance phase. These results suggest that SR 57746A specifically attenuates age‐related short‐term memory impairment in rats. © 1995 Wiley‐Liss, Inc.
Adenosine A1 receptors in rat brain synaptosomes: Transductional mechanisms, effects on glutamate release, and preservation after metabolic inhibition
Authors: Abbracchio Maria P. , Brambilla Roberta , Camisa Manuela , Rovati G. Enrico , Ferrari Rosaria , Canevari Laura , Dagani Fiorenzo , Cattabeni Flaminio 
Published: January 2005

AbstractSynaptosomes from various rat brain areas show saturable and specific binding to an adenosine A1 receptor ligand [Dagani et al. (1993): Drug Dev Res 28:359–363]. In this study, the functional correlates of these receptors were characterized in rat hippocampal synaptosomes by evaluating the ability of the adenosine analogue cyclo‐pentyl‐adenosine (CPA) to modulate KCI‐ and veratridine‐induced glutamate outflow. CPA concentration‐dependently reduced both depolarization‐induced glutamate release and the associated increases of intrasynaptosomal Ca2+ concentrations. Maximal reduction by 100 μM CPA (30% and 40% with respect to control for veratridine‐ and KCI‐induced release, respectively) was completely antagonized by the xanthine adenosine receptor blocker bamyfilline, confirming the involvement of adenosine A1 receptors. CPA selectively affected outflow of glutamate, with no significant influence on release of aspartate or GABA. Experiments performed in the absence of extrasynaptosomal Ca2+ ions suggested that adenosine selectively modulates glutamate Ca2+ ‐dependent vesicular pool. Transductional studies showed that mobilization of Ca2+ from intrasynaptosomal inositol‐phosphate‐sensitive stores does not contribute to adenosine effects on release, therefore implying that CPA reduction of Ca2+ influx is due to direct effects on membrane Ca2+ conductance. Conversely, activation of A1 receptors resulted in inhibition of forskolin‐stimulated cAMP production in the same agonist concentration range effective on modulation of release, suggesting that this second messenger may play a role in the presynaptic effects of adenosine analogues. Finally, CPA reduced both glutamate efflux and the increases of internal Ca2+ concentrations associated with block of synaptosomal energy metabolism with rotenone and iodoacetic acid, suggesting that presynaptic A1 receptors represent a strategic site of action for adenosine also under experimental conditions resembling brain ischemia and hypoxia. © 1995 Wiley‐Liss, Inc.
A‐80426, a potent and selective α2‐adrenoceptor antagonist with serotonin uptake‐blocking activity and putative antidepressant‐like effects: II. Pharmacology profile
Authors: Giardina William J. , Buckner Steven A. , Brune Michael E. , Hancock Arthur A. , Wismer Carol T. , Milicic Ivan , Rattin Anthony J. , Roux Sylvain , Wettstein Joseph G. , Meyer Michael D. , Porsolt Roger D. , Kerwin James F. , Williams Michael 
Published: January 2005

AbstractA‐80426 N‐[2‐(benzofuran‐6‐yl)ethyl]‐N‐[(R)−( + (‐5‐methoxy‐1,2,3,4‐tetrahydronaphthalen‐1‐yl methyl]‐N‐methylamine) is a compound that combines in vitro selective inhibition of serotonin synaptosomal uptake and α2‐adrenoceptor antagonism. In the present studies, A‐80426 was evaluated in vivo for its ability to block serotonin uptake and α2‐adrenoceptors. The antidepressant potential of the compound was also assessed.In rats, A‐80426 significantly reduced p‐chloroamphetamine (PCA)‐induced hyperactivity, a measure of the in vivo blockade of serotonin uptake, after acute (ED50 = 13 μmoles/kg, po) and chronic (14 day) (ED50 = 4.1 μmoles/kg, po) dosing. At doses of 6.7 and 22 μmoles/kg, po, A‐80426 was effective in this test procedure for at least 12 h following administration. Doses of 6.7 to 224 μmoles/kg, ip, of A‐80426, however, failed to block hypothermia and hypoactivity produced by the α2‐adrenoceptor agonist clonidine, and doses of 100 and 300 μmoles/kg, po, were required to blocked clonidine‐induced mydriasis. Thus, the in vitro α2 receptor binding and blocking effects observed with A‐80426 did not translate into the in vivo situation.A‐80426 was able to reverse the step‐down passive avoidance deficit seen in olfactory bulbectomized rats (ED70 = 7.1 μmoles/kg, po), a finding suggesting that the compound has antidepressant potential. The compound was, however, inactive in the tail suspension and forced swim tests of antidepressant activity in mice at doses up to 72 μmoles/kg, ip. In contrast, fluoxetine was active in all three paradigms.Despite its favorable in vitro profile, A‐80426 is not an effective α2 blocker in vivo and is inactive in the behavioral dispair models of depression. It is unlikely that A‐80426 would have antidepressant activity equivalent to existing selective serotonin reuptake inhibitors. α2 blockade as a potential approach to eliciting antidepressant activity is discussed. © 1995 Wiley‐Liss, Inc.
Structure‐activity studies of analogs of β, γ‐methylene‐ATP at P2X‐purinoceptors in the rabbit ear central artery
Authors: Martin Pauline L. , Gero Thomas W. , Potts Alice Anne , Cusack Noel J. 
Published: January 2005

AbstractStructure‐activity studies using naphthylmethyl analogs of β, γ‐methylene‐ATP were conducted at the P2X‐purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α, β‐m‐ATP. On the adenine base, substitution at the C2‐position (WRC‐0440) increased the agonist potency 2‐fold and substitution at the C8‐position (WRC‐0431) did not change agonist potency, and both compounds had the same maximal response as β, γ‐m‐ATP, whereas substitution at the N6‐position (WRC‐0416) abolished activity. On the D‐ribose sugar, substitution on the 2′‐hydroxyl generated a partial agonist (WRC‐0479), which had a maximal effect of only 39% of that of β‐γ‐m‐ATP. Attempts to substitute the 3′‐hydroxyls by naphthylmethyl failed, but substitution by p‐methoxybenzyl (WRC‐0617) did not change potency or the maximal response. Cyclic substitution of both the 2′‐ and 3′‐hydroxyls by naphthylmethylidine (WRC‐0498) had no effect on the agonist potency or the maximal response relative to β‐γ‐m‐ATP. On the β, γ‐methylenetriphosphonate chain, substitution on the methylene linkage by naphthylmethyl (WRC‐0433) had no effect on agonist potency, but the maximal response increased to 122% that of β‐γ‐ATP. However, the contractile response to WRC‐0433 was not desensitized by α, β‐γ‐ATP (contractile responses to all other agonists were abolished by α‐β‐γ‐ATP pretreatment), but was blocked by the α1 antagonist prazosin (10−6 M). WRC‐0433 appears to act at a prejunctional site that mediates ATP‐induced release of norepinephrine. Purine nucleotides with substituents at the 2′‐position of the ribose sugar could provide a lead to the generation of P2X‐purinoceptor antagonists. © 1995 Wiley‐Liss, Inc.
Development of postural asymmetry in premature human infants
Authors: Gardner Judith , Lewkowicz David , Turkewitz Gerald 
Published: January 2005

AbstractThe head position of 95 infants, born between 30 and 37 weeks gestational age, was observed every 15 min for 2 hr weekly from birth until 39 weeks conceptional age. At 35 weeks and increasingly thereafter, significantly more time was spent with the head to the right than to the left. By 39 weeks the infants were similar to term infants: almost 90% spent 80% or more time with their heads to the right. The increase appeared independent of intra‐ or extrauterine experience; neither age at birth nor time since birth was consistently related to head position. Unlike term infants, prematures were equally likely to turn left as right and have their heads left as right 15 min after release from a midline position. These findings suggest complex determinants of asymmetry including factors intrinsic to the fetus and those contributed by the uterine environment.
Diurnal cortisol and temperature variation of normal and autistic children
Authors: Hill Suzanne D. , Wagner Emily A. , Shedlarski Joseph G. , Sears Suzanne P. 
Published: January 2005

AbstractBlood samples and temperature measurements were taken over a 24‐hr period for 6 children with autistic features and 3 normal control children of approximately the same age. The normal children showed relatively adult diurnal rhythmicity in cortisol and temperature. In contrast, 4 of 6 autistic children showed abnormal patterns in both measures.