bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Metabolism of a Series of Ester Pro-drugs by NCTC 2544 Cells, Skin Homogenate and LDE Testskin
Authors: Lamb K A , Denyer S P , Sanderson F D , Shaw P N 
Published: April 2011

Abstract
The metabolism of a series of substituted pyrazolopyridine ester pro-drugs was investigated using NCTC 2544 cells, human skin homogenate and LDE Testskin as model systems. The compounds were incubated in each system and the disappearance of drug and the production of the major hydrolysis product was observed with time and quantitated using HPLC. The toxicity of the ester pro-drugs and the metabolites was examined in NCTC 2544 cells using a cell viability assay procedure. Hydrolytic activity was slightly higher in the cell culture model than in skin homogenate solution but the rank order of activity for each pro-drug was similar. The metabolic activity of LDE Testskin was much reduced compared with the other systems, but again the overall pattern of metabolism was not dissimilar. These findings indicate that NCTC 2544 cells provide a reasonable model for human skin ester hydrolysis both in terms of rate and in terms of substrate specificity.
Liposomes as In-vivo Carriers for Citicoline: Effects on Rat Cerebral Post-ischaemic Reperfusion
Authors: Fresta Massimo , Puglisi Giovanni , Di Giacomo Claudia , Russo Alessandra 
Published: April 2011

Abstract
Citicoline is a therapeutic agent widely used in the treatment of brain injury, for example in cerebrovascular disease or traumatic accidents. Unfortunately, the strong polar nature of this drug prevents it crossing the blood-brain barrier. In this paper, the possibility of efficiently trapping citicoline in liposomes to improve its therapeutic effects is reported. The citicoline-encapsulation efficiency, drug leakage and size analysis of various liposome systems were studied. The real therapeutic effectiveness of these citicoline liposome formulations was evaluated by biological assay. The effects of free and liposome encapsulated citicoline on survival rate of ischaemic reperfused male Wistar rats (80–100 g) were investigated. Of the phospholipid mixtures used in citicoline liposome formulation the best in terms of delivery and therapeutic effects was 1,2-dipalmitoyl-sn-glycero-phosphocholine:dipalmitoyl-dl-α-phosphatidyl-l-serine: cholesterol (7:4:7 molar ratio). This phospholipid mixture was also assayed for brain conjugated diene levels in rats, since this parameter is an index of lipid peroxidation in rat cerebral cortex during post-ischaemic reperfusion. A citicoline-loaded phospholipid mixture has produced an increase in rat survival rate of about 24% and a reduction in diene levels of 60%, compared to the free drug.
Kojic Acid, a Cosmetic Skin Whitening Agent, is a Slow-binding Inhibitor of Catecholase Activity of Tyrosinase
Authors: Cabanes Juana , Chazarra Soledad , Garcia-Carmona Francisco 
Published: April 2011

Abstract
It was found that kojic acid, which is used in cosmetics for its excellent whitening effect, inhibits catecholase activity of tyrosinase in a non-classical manner. A decrease in the initial velocity to a steady-state inhibited velocity can be observed over a few minutes. This time-dependence, which is unaltered by prior incubation of the enzyme with the inhibitor, is consistent with a first-order transition. The kinetic data obtained correspond to those for a postulated mechanism that involves the rapid formation of an enzyme inhibitor complex that subsequently undergoes a relatively slow reversible reaction. Kinetic parameters characterizing this type of inhibition were evaluated by means of nonlinear regression of product accumulation curves.
Physicochemical Characterization and Acute Toxicity Evaluation of a Positively-charged Submicron Emulsion Vehicle
Authors: Klang Shmuel H , Frucht-Pery Joseph , Hoffman Amnon , Benita Shimon 
Published: April 2011

Abstract
Fine, homogeneous, positively-charged emulsions with a mean droplet size of 138 ± 71 nm and a zeta potential value of 41.06 mV were prepared using a combination of emulsifiers comprising phospholipids, poloxamer 188, and stearylamine. The pH of these emulsions decreased with time. However, the extent of decrease was dependent on the storage temperature. The mean droplet size of the emulsions that had been prepared with 1% poloxamer began to increase slightly after six months’ storage, particularly when stored at 23 and 37°C. However, emulsions prepared with 2% poloxamer remained stable for at least 10 months at 4°C, suggesting that the poloxamer 188 concentration is critical for prolonged emulsion stability. The results of the ocular tolerance study in rabbit eye indicate that hourly administration of a positively-charged emulsion vehicle was well tolerated without any toxic or inflammatory response to the ocular surface during the five days of the study. Scanning electron microscopy revealed a normal corneal surface, which was not different from that of the animals treated with physiological saline. No marked acute toxicity was observed when 0.6 mL of positively-charged emulsion was injected intravenously to BALB/c mice. Furthermore, no difference was noted between this group of animals and the group injected with the marketed Intralipid emulsion. These results were further confirmed in a rat study where there were no deaths following intravenous injection of 3.3 mL per rat of the positively-charged emulsion or Intralipid. Neither emulsion elicited any hepatotoxic or nephrotoxic effects. The overall results suggest that the novel positively-charged emulsion is suitable for parenteral use, and for ocular application.
Lipophilicity of Teicoplanin Antibiotics as Assessed by Reversed Phase High-performance Liquid Chromatography: Quantitative Structure-property and Structure-activity Relationships
Authors: Altomare Cosimo , Carotti Angelo , Cellamare Saverio , Carrieri Antonio , Ciabatti Romeo , Malabarba Adriano 
Published: April 2011

Abstract
Structure-lipophilicity relationships of a large series of 63-COX teicoplanin antibiotic derivatives were examined, by correlating their capacity factors (log kw), measured through reversed-phase high-performance liquid chromatography on Deltabond C8 stationary phase, with some computed molecular properties such as fragmental log P constants (***x), molecular volumes (Vx) and factors imparting hydrophilicity (e.g. amino groups in the X chain, nN). A number of equations were derived which demonstrate that variations of log kw are mainly related to changes in bulk (modelled by Vx) and polarity (primarily modelled by nN) of X chains of teicoplanin derivatives. QSAR analysis revealed that in-vitro activity against E. coli increases as lipophilicity decreases and isoelectric point increases.
Iron-binding Affinity of Bacterial Vaccine Polysaccharides which Contain Phosphodiester Linkages as Part of the Polymer Chain and of Other Polyphosphates, Including DNA
Authors: Bingham B R , Quinlan G J , Tarelli E 
Published: April 2011

Abstract
The interaction of iron (II) with bacterial polysaccharides, possessing phosphodiester bonds as part of their polymer chain, has been studied by equilibrium binding dialysis using atomic absorption spectrophotometry. Ferrous ions were found to bind with a stoichiometry of one per two phosphates and with a binding constant of about 2.5 times 103 M−1. Similar results, but with larger (ca 1 times 104 M−1) binding constants were observed with DNA. This interaction helps explain the depolymerization of polyphosphates which has been observed in the presence of iron salts, and highlights the need to avoid iron contamination of vaccines (and other substances) which contain phosphodiester bonds. The interaction may also be a means of iron sequestration in bacteria which possess these cell-surface polyphosphates.
Continuous Administration of Low Dose Rates of Physostigmine and Hyoscine to Guinea-pigs Prevents the Toxicity and Reduces the Incapacitation Produced by Soman Poisoning
Authors: Wetherell Janet R 
Published: April 2011

Abstract
A regime was developed, using mini-osmotic pumps, for the continuous subcutaneous administration of low doses of physostigmine (12.1, 9.7, 4.85 and 2.43 μgh−1), in combination with hyoscine (1.94 or 0.39 μg h−1), to guinea-pigs for up to 13 days. Physostigmine, in combination with hyoscine, inhibited plasma Cholinesterase, and red blood cell and brain acetylcholinesterase, in a concentration-dependent manner, did not affect the normal growth rate of guinea-pigs, and produced no obvious signs of poisoning. A dose rate of 4.85 μg h−1 physostigmine and 1.94 μg h−1 hyoscine was required to inhibit red cell acetylcholinesterase by 30% and brain acetylcholinesterase by 5–15%, with an accompanying plasma hyoscine concentration of 700–850 pg mL−1. There was an apparent decline in red cell acetylcholinesterase activity during the 13 days. Hyoscine levels were higher in the cholinergic-rich areas of the brain than in the plasma. Continuous pretreatment (1 or 6 days) with physostigmine (4.84 μg h−1) and hyoscine (1.94 μg h−1) provided complete protection against the lethal effects, and minimized the incapacitation and weight loss produced by soman at a dose equivalent to the LD99 value. Following soman challenge, guinea-pigs exhibited early signs of soman poisoning, but generally these signs of poisoning were minimal by 1–2 h. Extending the pretreatment time to 13 days protected 75% of the guinea-pigs against the lethal effects of soman poisoning. Red cell acetylcholinesterase activity, 24 h after soman poisoning, was higher following continuous pretreatment with physostigmine and hyoscine than after acute treatment with atropine.
Use of Powdered Cellulose for the Production of Pellets by Extrusion/Spheronization
Authors: Lindner H , Kleinebudde P 
Published: April 2011

Abstract
The use of powdered cellulose instead of microcrystalline cellulose in the extrusion/spheronization process was investigated. The aim of the study was to assess differences between two types of powdered cellulose using a 24–1 fractional factorial design. Water content and amount of binder were found to be most important while type of cellulose and screw speed had only negligible influence on the extrusion process and the resulting pellets. Pellets obtained with powdered celluloses showed higher porosities and faster dissolution rates compared with those made with microcrystalline cellulose. Image analysis was found to be an appropriate method for the simultaneous characterization of pellet size and shape.
Glutaraldehyde Cross-linked Bovine Casein Microspheres as a Matrix for the Controlled Release of Theophylline: In-vitro Studies
Authors: Latha M S , Jayakrishnan A 
Published: April 2011

Abstract
A controlled release dosage form of theophylline in the form of microspheres using the milk protein casein as the matrix is described. Glutaraldehyde cross-linking of an aqueous alkaline solution of the protein containing the drug, dispersed in a mixture of dichloromethane/hexane having ca. 1% of an aliphatic polyurethane as the suspension stabilizer, led to the formation of the drug-loaded microspheres. Drug incorporation efficiency of around 80% could be achieved by the technique. Release profiles of the drug were examined in simulated gastric and intestinal fluids at 37°C. It was observed that the release was diffusion-controlled and followed the Higuchi model. Release characteristics were influenced by the cross-linking density, particle size and the extent of loading. Data obtained indicate that the natural milk protein casein could be used as a matrix for sustained release oral dosage forms.
A Study of the Percutaneous Absorption-enhancing Effects of Cyclodextrin Derivatives in Rats
Authors: Vollmer U , Müller B W , Peeters J , Mesens J , Wilffert B , Peters T 
Published: April 2011

Abstract
2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) and 2,6-dimethyl-β-cyclodextrin (D-β-CyD) were studied for transdermal penetration enhancement of the cytochrome P450 inhibitor liarozole by an in-vivo transdermal absorption rat model. The mode of action of penetration enhancement was investigated by differential scanning calorimetry (DSC). In-vivo, HP-β-CyD, as a 20% aqueous solution, increased the absorption of liarozole approximately threefold and a 20% aqueous solution of D-β-CyD decreased the percutaneous absorption of liarozole in blood by a factor of 0·6. However, pretreatment with D-β-CyD (20%, 4 h) enhanced the transdermal absorption 9·4-fold. In the DSC experiments the thermal profile of human stratum corneum was practically unchanged after treatment with HP-β-CyD, but treatment with D-β-CyD revealed an interaction of D-β-CyD with the protein and lipid fraction. Thus the results from DSC and those from the permeability experiments revealed that D-β-CyD acts as a transdermal absorption enhancer by changing the stratum corneum barrier whereas HP-β-CyD influences the partitioning behaviour of the drug in the skin.
Metabolism and Transport of the Pentapeptide Metkephamid by Brush-border Membrane Vesicles of Rat Intestine
Authors: Langguth Peter , Bohner Viviane , Biber Jürg , Merkle Hans P. 
Published: April 2011

Abstract
Intestinal metabolism and transport of the pentapeptide metkephamid (Tyr-d-Ala-Gly-Phe-N-Me-Met-NH2) were studied using isolated brush-border membranes from the rat. Analysis of the metabolic fragments of enzymatic hydrolysis revealed that cleavage of the N-terminal peptide bond leads to the formation of tyrosine and a tetrapeptide d-Ala-Gly-Phe-N-Me-Met-NH2. The inactivation was due to aminopeptidase N activity and could be inhibited by peptidase inhibitors puromycin, bacitracin and certain dipeptides. Transport studies demonstrated uptake of the intact pentapeptide into the intra vesicular space of the vesicles. The transport was a first-order process; no participation of known intestinal peptide carrier systems in the transport of metkephamid could be shown. Modelling of simultaneous metabolism and transport kinetics suggests strategies to improve the fraction absorbed of a peptide by either decreasing its affinity to the metabolizing enzymes (increase Km) or decreasing the concentration of the metabolizing enzymes e.g. by delivering the peptide to an absorption site with reduced enzymatic activity (decrease Vmax) or increasing its absorption velocity.
Antihypertensive Action of Geraniin in Rats
Authors: Cheng Juei-Tang , Chang Shu-Shi , Hsu Feng-Lin 
Published: April 2011

Abstract
The effects of geraniin, one of the ellagitannins purified from the leaves of Sapium sebiferum, on blood pressure were investigated in the spontaneously hypertensive rat (SHR). A single intravenous bolus injection of geraniin into anaesthetized SHRs lowered the arterial mean blood pressure in a dose-dependent manner without affecting the heart rate. A similar action was also observed in the normotensive (WKY) rat that received this compound at a higher dose. Geraniin did not modify the baroflex sensitivity in the phenylephrine-challenged SHR. This tannin reduced the plasma noradrenaline in a dose-dependent fashion which was not influenced by adrenalectomy. Failure of the antagonists, idazoxan and yohimbine for α2-adrenoceptors as well as haloperidol and domperidone for dopamine receptors, to reverse the antihypertensive actions of geraniin ruled out the possible mediation of these receptors. Moreover, geraniin attenuated the pressor responses to exogenous noradrenaline and Bay K 8644 to a similar degree, indicating the direct effect of this compound on vascular activity in rats. These results suggest that geraniin possesses the ability to lower systemic blood pressure through the reduction of noradrenaline release or by direct vasorelaxation.
Antithyroid Action of Ketoconazole: In-vitro Studies and Rat In-vivo Studies
Authors: Comby Francis , Lagorce Jean-François , Buxeraud Jacques , Raby Claude 
Published: April 2011

Abstract
Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol−1), and to inhibit lactoperoxidase (IC50 2 × 10−4 m). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.
Inhibition of Platelet Thromboxane Formation and Phosphoinositides Breakdown by Diisoeugenol
Authors: Lin Chien-Huang , Kuo Yeh-Hsiong , Lin Yun-Lian , Teng Che-Ming 
Published: April 2011

Abstract
Diisoeugenol inhibited the platelet aggregation and ATP release of rabbit platelets caused by ADP, arachidonic acid, platelet-activating factor (PAF), collagen and thrombin. Prolongation of the incubation time of platelets with diisoeugenol did not cause further inhibition and the aggregability of platelets could not be restored after washing. In human platelet-rich plasma, diisoeugenol inhibited the biphasic aggregation and ATP release induced by adrenaline and ADP in a concentration-dependent manner. Thromboxane B2 formation caused by arachidonic acid, collagen and thrombin was markedly inhibited by diisoeugenol in a concentration-dependent manner. Diisoeugenol also inhibited the formation of inositol monophosphate caused by collagen, PAF and thrombin. The cAMP level of washed platelets was not changed by diisoeugenol. It is concluded that the antiplatelet effect of diisoeugenol is due to the inhibition of thromboxane formation and phosphoinositides breakdown.
Salmeterol inhibits anaphylactic histamine release from guinea-pig isolated mast cells
Authors: Gentilini Grazia , Di Bello Maria Grazia , Raspanti Silvia , Bindi Daniela , Mugnai Sabrina , Zilletti Lucilla 
Published: April 2011

Abstract
Salmeterol (1 Nm-100μm) showed an inhibitory action on anaphylactic histamine release from mast cells, isolated from pleural and peritoneal cavities of actively sensitized guinea-pigs and stimulated by incubation with allergen. The effect is concentration-dependent and is reduced by the β-adrenoceptor antagonist propranolol (1 μm). This study supports the hypothesis of an antiinflammatory property of salmeterol, which concerns cells involved in the early phases of asthma.
Gastrointestinal Effects of Diazepam-withdrawal are Linked to Activation of Central Cholecystokinin-ergic Pathways in Rats
Authors: Bonnafous Cécile , Martinez Jose , Bueno Lionel 
Published: April 2011

Abstract
The influence of flumazenil-precipitated diazepam withdrawal on intestinal myoelectric activity and colonic transit was evaluated, in diazepam-dependent rats. Administered intraperitoneally, flumazenil (15 mg kg−1) induced a strong stimulation of the duodenal spiking activity lasting 197 ± 20 min, and accelerated colonic transit corresponding to a significantly (P &lt; 0·05) increased value of the geometric centre (3.52 ± 0.23 vs 2·44 ± 0·1 for the control). Both devazepide and L365260 administered intracerebroventricularly at a dose of 10 μg kg−1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 μg kg−1) only L365260 was able to antagonize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit when administered intracerebroventricularly at a dose of 10 μg kg−1, whereas similar blockade was obtained at a dose of 5 μg kg−I with L365260, and 10 ng kg−1 with PD135–158. It is concluded that in rats precipitated diazepam-withdrawal altered intestinal motility and colonic transit and that these effects are mediated by central release of cholecystokinin (CCK) or activation of CCK-ergic neurons.
The Adenosine Agonist NECA Inhibits Intestinal Secretion and Peristalsis
Authors: Coupar Ian M , Hancock Debra L 
Published: April 2011

Abstract
This study aimed to determine whether the antidiarrhoeal effect of the mixed A1/A2 adenosine agonist NECA (5′-N-ethylcarboxamido adenosine) is due to inhibition of intestinal fluid transport or to contractility. Intestinal secretion was stimulated in anaesthetized rats by intra-arterial infusions of PGE2 (4 μg min−1) or vasoactive intestinal peptide (0·8 μg min−1). NECA reversed PGE2-induced secretion in the jejunum (ED50 16 μg kg−1) and ileum (ED50 21 μg kg−1, i.v.) and inhibited VIP-induced secretion in the jejunum (ED50 21·5 μg kg−1). NECA inhibited twitch responses (0·1 Hz, 1 ms, IC50 11·2Nm) but not tetanic contractions at 10 Hz of the transmurally stimulated guinea-pig ileum. Likewise, NECA (10 μm) did not inhibit frequency-related contractions over the range of 2·5 to 40 Hz of rat jejunum or ileum. However, NECA was shown to be a potent inhibitor (30 Nm) of the peristaltic reflex in the rat ileum. The results indicate that adenosine receptors are involved in modulating peristalsis as well as the secretory activity of the mucosa in the rat small intestine.
Evidence for Functional δ-Opiate Receptors in the Rat Intestine
Authors: Hancock Debra L , Coupar Ian M 
Published: April 2011

Abstract
The selective δ-opiate agonists d-Ser2, Leu5, Thr6-enkephalin (DSLET), d-Ala2, d-Leu5-enkephalin and d-Pen2, d-Pen5-enkephalin caused inhibition of the cholinergic contraction produced by transmural stimulation of the rat isolated jejunum. Dynorphin A, which is an agonist at both κ- and δ-opioid receptors also inhibited the cholinergic contraction, as did leu- and met-enkephalin. The selective μ-receptor agonist d-Ala2-NMe-Phe4, Gly-ol5-enkephalin was the least potent of all peptides tested. In general, the order of potency of the peptides was similar to that reported for the δ-receptor-rich mouse vas deferens with potency values similar to those recorded previously for the hamster vas deferens. The selective δ-opioid antagonist naltrindole caused parallel shifts to the concentration-effect curve to DSLET giving a pA2 value of 10·15. The results indicate that the previously identified δ-binding sites in the rat jejunum may correspond to functional δ-opiate receptors involved in attenuating acetylcholine release.
The Action of 1,2,3,5,6,11b-Hexahydro-[1]benzothieno [3,2-g]indolizine Hydrochloride (ADT 16) on Peripheral and Central Responses Mediated by 5-Hydroxytryptaminergic and Adrenergic Systems of the Rat
Authors: Leitch I M , Rawlow A , King R G , Boura A L A , Bremner J B , Browne E J 
Published: April 2011

Abstract
Some acute pharmacological effects have been examined of racemic ADT 16 (1,2,3,5,6,11b-hexahydro[1]benzothieno[3,2-g]indolizine hydrochloride), on peripheral and central responses mediated by 5-HT and adrenergic systems in the rat. In-vitro, ADT 16(10–1000 Nm), similarly to mianserin, antagonized the inhibitory responses to B-HT 920 of the electrically-stimulated rat isolated prostatic vas deferens. High concentrations of ADT 16 (10 μm), also resembled those of mianserin by potentiating twitch responses to electrical stimulation of the tissue. Contractile responses to phenylephrine of rat isolated epididymal vas deferens were antagonized by ADT 16 (0·3–1 μm). In the rat stomach fundus strip, ADT 16 (1–3 μm) antagonized contractions due to 5-HT. ADT 16 (0·1–1 μm) had no effect on responses to acetylcholine of the guinea-pig isolated ileum. In-vivo, in spinalized, decerebrated rats, fenfluramine- or clonidine-induced facilitation of flexor reflex activity of the anterior tibialis muscle was attenuated by ADT 16 (3 and 10 mg kg−1, i.v., and 3 mg kg−1, i.v. respectively). In the anaesthetized rat, l-3,4-dihydroxyphenylalanine (l-dopa)- or l-5-hydroxytryptophan (l-5-HTP)-induced increases in the frequency of spontaneous twitches of the anterior digastricus muscle were attenuated by ADT 16 (1 and 3 mg kg−1, i.v.; n = 4). It is concluded that ADT 16, similarly to mianserin, is a novel peripherally and centrally active antagonist of 5-HT and adrenergic responses in the rat.