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P Strong

Publications and source records attributed to P Strong.

At least 55 records · Page 3Linked to original sources
PubMed1994

Structural determination and packing analysis of a cholesteryl caprate/cholesteryl laurate solid solution.

This paper describes the X-ray crystal structure analysis of a cholesteryl ester solid solution, cholesteryl decanoate/cholesteryl laurate, grown from a bulk concentration with molar ratio 0.56/0.43. The unit cell is monoclinic with a = 12.969, b = 9.048, c = 31.137 A, and beta = 91.12 degrees and the space group P2(1) with Z = 4 (two molecules per asymmetric unit). The cell constants closely represent an average value of crystal parameters for the two pure components (hence, nearly corresponding to Vegard's law). Although the overall monolayer 1 lamellar packing is superficially similar to the earlier-studied cholesteryl undecanoate/cholesteryl laurate solid solution, a more partitioned distribution of acyl chains, i.e., a microfractionation corresponding to the observed nonideal phase behavior, is suggested. The behavior is similar to that found for n-paraffin binaries cooled below a binodal phase boundary. Although it cannot be detected conclusively in this determination (due to high thermal motion of terminal acyl chain atoms), the non-stoichiometric combination of components also requires some partial occupancy of atomic sites on the chain termini. This structural arrangement is contrasted with the alternative expression found earlier for the more ideal undecanoate/laurate solid solution, i.e., random co-packing leading to fractional atomic occupancy in an average laurate structure. The final weighted R factor for 4578 reflections is 0.138.

Cholesterol Esters↗
PubMed1993

The pharmacology of salmeterol.

Salmeterol was developed to provide prolonged bronchodilatation to control nocturnal symptoms and improve maintenance therapy in asthmatic patients. Salmeterol is > 10,000 times more lipophilic than salbutamol and has greater affinity for the beta 2-adrenoceptor. Membrane binding is non-competitive and dissociation is slow so that its effects last for many hours. Despite this, salmeterol does not accumulate in tissues. Its mechanism of action can be explained by binding to a specific exo-site domain of the beta 2-receptor protein to produce continuous stimulation of the active site of the receptor, which gives salmeterol a profile of pharmacological activity unlike that of other beta 2-agonists. Due to its potent and prolonged activation of beta 2-adrenoceptors in airway smooth muscle cells, endothelial cells, mast cells and epithelial cells, salmeterol induces prolonged bronchodilatation, reduced vascular permeability, inhibition of inflammatory mediators, stimulation of ciliary function and modulation of ion and water transport across the bronchial mucosa.

Adrenergic beta-Agonists↗
PubMed1993

Suppression of non-esterified fatty acids and triacylglycerol in experimental animals by the adenosine analogue GR79236.

1. This is the first description of the metabolic activity of a novel adenosine A1-receptor agonist, GR79236. GR79236 inhibited catecholamine-induced lipolysis in human, rat and dog isolated adipocytes. 2. Oral administration of GR79236 (0.1-10 mg/kg) to fed rats induced minimal changes in the plasma concentration of non-esterified fatty acids and in the blood concentrations of glucose and lactate. 3. Intravenous infusion of GR79236 to fasted pithed rats, or oral administration of GR79236 to fasted conscious rats and dogs, produced time- and dose-dependent decreases in the plasma non-esterified fatty acid concentration. In the fasted rats, doses of GR79236 that lowered plasma levels of non-esterified fatty acids also produced hypotriglyceridaemia and anti-ketotic effects. 4. Only in the pithed rats were acute effects on the plasma glucose and lactate concentrations observed. Hypoglycaemia and hyperlactataemia occurred over the dose range studied (1 x 10(-11)-1 x 10(-8) mol min-1 kg-1). 5. This profile of activity suggests that compounds such as GR79236 might be agents which can be used to define the role of excessive lipolysis in experimental (and human) pathophysiology.

Adenosine↗
PubMed1993

Early histological features of small intestinal injury induced by indomethacin.

The early histological features of indomethacin-induced jejunal injury in the rat are described in tissues preserved by perfusion-fixation with 10% formol-saline. After an oral dose of indomethacin (15 mg/kg, known to cause severe multifocal ulceration of the rat jejunum), groups of rats were anaesthetized with subsequent perfusion-fixation of the gastrointestinal tract at 1, 2, 3, 6 and 48 h after dosing. Using routine light microscopic techniques, we have observed a sequence of four distinct stages, in time, of small intestinal injury. The earliest histological features were shortening of the villi, epithelial stratification, basal lamina degeneration, eosinophil degranulation and infiltration of the epithelium prior to infiltration of the mucosa by neutrophils. We consider that these earliest changes, seen at 1, 2 and 3 h, represent a distinct histological entity termed Type 1 change or villous 'tufting'. Type 2 change includes all of the features of Type 1 change plus the subsequent infiltration of the mucosa by neutrophils at 2, 3 and 6 h. Type 3 change includes necrosis of the upper-third of the villi and was mainly seen at 3 and 6 h. Type 4 change describes extreme injury to more than one-third of the mucosa with severe, acute inflammation and perforation of the bowel wall by 48 h. Although a small number of neutrophils had appeared to infiltrate the mucosa as early as 2 h after dosing, they were only significantly increased at 3, 6 and 48 h. Possible pathogenic mechanisms involved in shortening of villi as a result of smooth muscle contraction and the role of mucosal eosinophils in NSAID-induced jejunal injury in the rat are discussed.

Animals↗
PubMed1993

Functional characterization of three adenosine receptor types.

1. The purpose of the present study was to classify adenosine receptors into A1 and A2 subtypes in a wide range of isolated tissues and cell types (rat adipocytes and atria, guinea-pig ileum and atria (A1); guinea-pig aorta, dog coronary artery and human platelets and neutrophils (A2)) using the R- and S-diastereoisomers of N-phenylisopropyladenosine (PIA), N-cyclopentyladenosine (CPA), the novel compound, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236), N-[(2-methylphenyl)methyl]adenosine (metrifudil), 2-(phenylamino)adenosine (CV1808), and 2[[2-[4-(2-carboxyethyl)phenyl]ethyl]amino]-N- ethylcarboxamidoadenosine (CGS21680); N-ethylcarboxamidoadenosine (NECA) was used as a standard. 2. Results obtained in all tissue preparations previously reported to contain A1-receptors could be described by a single rank order of agonist potency: CPA > or = GR79236, R-PIA > or = NECA >> S-PAI > or = metrifudil > or = CV1808, CGS21680. 3. In contrast, two distinct rank orders of agonist potency were observed in preparations previously reported to contain A2-receptors. In dog coronary artery, human neutrophils and platelets the rank order of potency was: CV1808, CGS21680 > or = NECA > R-PIA > or = metrifudil > or = CPA > GR79236 S-PIA. However, in guinea-pig aorta the rank order was: NECA > metrifudil > R-PIA, CPA > CV1808, GR79236 > or = S-PIA, CGS21680. 4. The results of this study are consistent with the existence of three types of adenosine receptor: A1-and two subtypes of A2-receptor. The receptor present in dog coronary artery, human platelets and neutrophils, probably corresponds to the A2a subtype, whilst that present in the guinea-pig aorta may be of the A2b subtype.

Adenosine↗
PubMed1993

Characterization of the adenosine receptor mediating contraction in rat colonic muscularis mucosae.

1. The objective of this study was to characterize the adenosine receptor mediating contraction in rat isolated colonic muscularis mucosae (RCMM). 2. Sequential additions of the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA; 0.01-10 microM) elicited reproducible, concentration-related contractions in RCMM. The effects of NECA were mimicked by the adenosine A1 receptor-selective agonists cyclopentyladenosine (CPA), R-phenylisopropyladenosine (R-PIA) and N-[1S, trans)2-hydroxycyclopentyl] adenosine (GR79236) and by S-PIA (the stereoisomer of R-PIA). The adenosine A2 agonists N-[(2-methylphenyl)methyl] adenosine (metrifudil) and 2-[p-(2-carboxyethyl)phenethylamine]-5'-N-ethylcarboxamidoadenosine (CGS21680) also produced contractions in RCMM but were 54 and 165 times less potent respectively than NECA. The rank order of agonist potency for contraction of RCMM was CPA > or = GR79236 = R-PIA > or = NECA > > S-PIA = metrifudil > CGS21680, which is identical to that reported for the inhibition of spontaneous rate in rat isolated right atria and inhibition of lipolysis in rat isolated adipocytes by these same agonists. 3. R-PIA, S-PIA and metrifudil behaved as partial agonists in RCMM. 4. The adenosine A1 receptor-selective antagonist 8-cyclopentyl-1,3- dipropylxanthine (DPCPX) inhibited the contractions produced by all the adenosine agonists tested, with pKB values between 9.2 and 9.5. The non-selective adenosine antagonist 8-phenyltheophylline (8-PT) antagonized the effects of NECA but also markedly potentiated (by 93.0 +/- 10.2% at 3 microM) the maximum contractile response to NECA in RCMM. Neither 8-PT (3 microM) nor DPCPX (0.1 microM) had any effect on the contractions produced by carbachol. 5. The contractile responses to NECA in RCMM were not affected by atropine (1 microM), tetrodotoxin(0.3 microM) or the P2 antagonist, suramin (100 microM).6. The present study confirms that contractions to adenosine agonists in the RCMM are mediated via adenosine Al receptors.

Adipocytes↗
PubMed1993

Do infiltrating neutrophils contribute to the pathogenesis of indomethacin induced ulceration of the rat gastric antrum?

The potential involvement of neutrophils in the pathogenesis of indomethacin induced ulceration of the gastric antrum in the re-fed rat was studied. Indomethacin was associated with a time dependent increase in the extent and severity of ulceration, blood neutrophilia, neutrophil infiltration into the gastric antrum, and calcium ionophore induced immunoreactive leukotriene B4 (LTB4) release from the antrum ex vivo. Neutrophil infiltration into the antrum was detectable 1 hour after dosing with indomethacin, at which time damage was apparent microscopically but not macroscopically. Thus, cell infiltration may contribute to the development, if not the initiation, of ulceration. Consistent with this suggestion, oral dexamethasone (5 mg/kg) significantly attenuated indomethacin induced ulceration, the associated neutrophil infiltration, and calcium ionophore induced immunoreactive leukotriene B4 release from the gastric antrum and whole blood ex vivo, although the blood neutrophilia was unaffected. These results suggest that indomethacin induced ulceration of the rat gastric antrum may have a dependence on neutrophil infiltration for its pathogenesis.

Animals↗
PubMed1992

Fasting in the rat does not induce hyperfibrinogenaemia.

The effects of fasting in the rat on the plasma fibrinogen concentration have been investigated. Fasting for 24-48 hr produced the expected sustained increase (4-5-fold) in the concentrations in the plasma of non-esterified fatty acids, but no accompanying increase in that of fibrinogen was detected.

Animals↗
PubMed1992

Crystal and molecular structure of the depsipeptide ionophore hexadecaisoleucinomycin, cyclo-[(D-Ile-L-Lac-L-Ile-D-Hyi)4-] (C80H136N8O24).

The crystal structure of a synthetic depsipeptide ionophore hexadecaisoleucinomycin, cyclo [-(D-Ile-L-Lac-L-Ile-D-Hyi)4-] (C80H136N8O24), has been determined by single crystal x-ray diffraction techniques. The crystals are orthorhombic, space group P2(1)2(1)2(1), number of molecules per unit cell z = 4, and cell parameters a = 11,195, b = 17.853, c = 54.835 A. The values of the standard (R) and weighted (Rw) discrepancy factors after refinement are 0.122 and 0.135, respectively. The structure is characterized by an elongated bracelet form with a twofold axis of pseudosymmetry. It is stabilized by eight intramolecular 4----1 hydrogen bonds between the amide C = O and N - H groups. The ester carbonyls are directed toward the inside of the molecule, their oxygen atoms forming an ellipsoidal internal cavity. The side chains are located on the molecular periphery. The conformational states of hexadecaisoleucinomycin in solution are discussed in the light of the data obtained.

Amino Acid Sequence↗
PubMed1992

Prostanoid-induced inhibition of lipolysis in rat isolated adipocytes: probable involvement of EP3 receptors.

Sulprostone, enprostil and 16, 16 dimethyl PGE2 have all been found to be potent inhibitors of lipolysis induced by 3-isobutyl-1-methyl-xanthine (IBMX) in rat isolated adipocytes. The potency of sulprostone and enprostil in particular indicates that the response is likely to be mediated through either EP3 or EP1-receptors. However, the EP1-receptor blocking drug, AH6809, had no effect on the antilipolytic response to either PGE2 or sulprostone. We therefore conclude that the receptors mediating prostanoid-induced inhibition of lipolysis in rat adipocytes must principally be of the EP3 sub-type.

Adipose Tissue↗
PubMed1992

Do adenosine A3 receptors exist?

1. It has been suggested that adenosine A1 receptors may be sub-divided into A1 and A3 types, based on the relative potencies of 5'-N-ethylcarboxamidoadenosine (NECA) and selected N6-substituted adenosine analogues. At A1 receptors (rat adipocytes) N6-phenylisopropyladenosine (PIA) was reported to be approx. 100-fold more potent than NECA, whereas the compounds were equipotent at A3 receptors (those in cardiac and neuronal preparations). 2. The study reported here has systematically evaluated this proposal, the rank orders of potency of NECA, R- and S-PIA, N6-cyclopentyladenosine (CPA) and N6-cyclohexyladenosine (CHA) being determined in rat adipocytes, guinea-pig ileum and rat and guinea-pig atria. 3. R-PIA, CHA and CPA were found to have consistent potencies relative to NECA across all 6 tissues, including rat adipocytes. The rank order was CPA greater than or equal to CHA, R-PIA greater than or equal to NECA greater than S-PIA. 4. We conclude that the relative potencies of these agonists do not support the concept that adenosine A1 receptors in rat adipocytes differ from those in neuronal and cardiac tissues.

Adenosine↗
PubMed1992

Molecular conformation of estramustine and two analogues.

The crystal and molecular structures of estramustine and two of its analogues have been determined by X-ray crystallographic techniques (a total of three different compounds). The compounds studied are estramustine [1,3,5(10)-estratriene-3,17 beta-diol-3-N,N-bis(2'- chloroethyl)carbamate] and its monohydrate, estromustine [17-oxo-1,3,5(10)-estratriene-3-yl-N,N-bis(2'-chloroethyl)carbamate], and 17-oxo-5-androsten-3 beta-yl-N,N-bis(2'-chloroethyl)carbamate. Three views of estramustine were obtained from the study of its two crystal forms. The main structural features found are as follows: (a) the geometries of the steroid moieties are closely similar to those of the parent steroids, (b) the bonds around the nitrogen atom of the nitrogen mustard grouping lie approximately in a plane in each structure, (c) the plane through the carbon atoms of the steroid A-ring lies approximately perpendicular to the plane through the carbamate atoms in each structure, (d) the carbonyl C-O of the carbamate points to the alpha side of the steroid moiety in each structure, and (e) one chlorine atom of the nitrogen mustard grouping makes a close contact [3.13 A], in each structure, to the nitrogen atom. Hydrogen bonding to the carbamate appears to occur from the alpha side of the steroid; there is no hydrogen bonding to the nitrogen atom of the carbamate group. These structural data provide some steric explanations for the resistance of the carbamate to enzymatic hydrolysis. The long in vivo half-life of the intact estramustine molecule is a result of this stability. This is responsible for the absence of alkylating ability and the propensity of the drug to bind microtubule-associated proteins and express an antimitotic mechanism of action.

Estramustine↗