bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical Basis for Deficient Paracetamol Glucuronidation in Cats: an Interspecies Comparison of Enzyme Constraint in Liver Microsomes
Authors: Court Michael H , Greenblatt David J 
Published: April 2011

Abstract
Unlike most other mammalian species, domestic cats glucuronidate phenolic compounds poorly and are therefore highly susceptible to the toxic side effects of many drugs, including paracetamol. In this study, we evaluated the role of enzyme constraint, a characteristic that limits the activity of all uridine 5′-diphosphoglucuronosyltransferase (UGT) enzymes, in the aetiology of this species-dependent defect of drug metabolism.
Detergent activation experiments were performed using hepatic microsomes from cats (4), dogs (4), man (4), and 6 other mammalian species (1 liver each). In addition, we used microsomes from Gunn rats which are sensitive to paracetamol toxicity because of a genetic defect affecting all family 1 UGTs. Increase in paracetamol-UGT activity at optimum concentrations of detergent was used as an index of enzyme constraint. Native activity (measured in the absence of detergent) was less than one-sixth in cats compared with other species. Optimum detergent treatment tended to enhance rather than abolish this difference, however, indicating relatively lower levels of constraint of paracetamol-UGT in cats compared with other species. Similarly, detergent treatment failed to reduce the native activity difference between homozygous mutant and normal Gunn rats. Initially CHAPS (3-(3-cholamidopropyl)-dimethylamrnonio-1-propanesulphonic acid) was used as the detergent activator; in 3 of 4 microsomal preparations from man, however, inhibition rather than activation was observed at all detergent concentrations used. Studies were repeated using the non-ionic detergent, Brij 58 (polyoxyethylene 20-cetyl ether), which resulted in similar although more profound activation and no inhibition.
We conclude that deficient paracetamol glucuronidation in cats does not result from increased paracetamol-UGT constraint in this species compared with other mammalian species. Other causes, such as differences in enzyme protein concentration or substrate affinity might be responsible.
The Effects of Lag-time and Dwell-time on the Compaction Properties of 1 : 1 ParacetamoUmicrocrystalline Cellulose Tablets Prepared by Pre-compression and Main Compression
Authors: Akande Oloniyon F , Ford James L , Rowe Philip H , Rubinstein Michael H 
Published: April 2011

Abstract
The effects of lag-time and dwell-time on the compaction properties of tablets compressed from a 1:1 blend of paracetamol and microcrystalline cellulose have been examined using a compaction simulator.
Increases in lag-times (from 0.06 to 0.53s) resulted in small increases in the tensile strengths of the tablets when combinations of 80 and 160MPa were used as the compression pressures. Further increases in lag-time did not alter the tablet strengths. When combinations of 240 and 320 MPa were used for pre-compression and main compression, the effects on the tensile strengths were more complex, partly because the high elastic recoveries of the tablets resulted in greater variability in the data. Increases in lag-times from 0.06 to 0.97 s resulted in an increase of between 12 and 28% in tensile strength. Longer lag-times (1.24 or 1.52s) did not result in further increases in tensile strength. The application of a dwell-time of 0.26 s during pre-compression or main compression pressures of 80 and 160 MPa generally led to a decrease (14–22%) in tensile strength compared with tablets where no dwell-time was used. This was because of increases in both the elastic recoveries and elastic energies. Subsequent increases in dwell-time from 0.26 to 0.9 s resulted in increases in tablet strength compared with that obtained when no dwell-time was applied. The tensile strengths of tablets made with a pre-compression of 160 MPa then a main compression of 80 MPa were 11–33% higher than those of tablets made with a pre-compression of 80 MPa then a main compression of 160 MPa. This was because higher plastic energies and more plastic deformation occurred at the higher pre-compression.
Generally, the application of dwell-time resulted in greater increases in tensile strengths than lag-time, which had less effect on the compaction properties.
Polyamine-mediated Heart Hypertrophy Induced by Clenbuterol in the Mouse
Authors: Cubría J C , Reguera R , Balaña-Fouce R , Ordónez C , Ordóñez D 
Published: April 2011

Abstract
The use of β-agonists as growth-promoting agents in cattle could lead to toxic side-effects in man. One such effect is the accumulation of polyamines which seem to be implicated in muscle and heart hypertrophy. We have studied the induction of cardiac hypertrophy after treatment with clenbuterol and the role of polyamines in this effect.
Treatment of mice with repeated doses of clenbuterol, a specific β-adrenergic agonist, resulted in a marked increase in heart muscle weight whereas total body weight did not change significantly. Clenbuterol-linked cardiac hypertrophy could be prevented by coadministration of either the non-specific β-adrenergic antagonist, propranolol, or the irreversible inhibitor of ornithine decarboxylase, α-difluoromethylornithine. The clenbuterol-induced cardiac hypertrophy was associated with a corresponding increase in the level of the polyamines putrescine, spermidine and spermine.
These observations are indicative of the role of polyamines in cardiac hypertrophy induced by clenbuterol.
Different Absorption Profiles of Deramciclane in Man and in Dog
Authors: Kanerva Harri , Klebovich Imre , Drabant Sandor , Urtti Arto , Nevalainen Timo 
Published: April 2011

Abstract
We have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid-labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in-vitro stability of deramciclane was determined over the pH range 1.2–6.0.
The rate of degradation of deramciclane increased ten-fold as the pH was reduced from 2.1 to 1.2 (t.β (elimination half-life) 9 h and 39 min, respectively). Deramciclane was stable at pH. 3. The two formulations were bioequivalent in dogs and there were no significant differences between pharmacokinetic parameters measured for dogs pretreated with pentagastrin or saline. In man the mean relative bioavailability and Cmax (peak plasma concentration) for the conventional capsules were approximately 75% and 83% of those for the enteric coated tablets (P = 0.0004 and P = 0.0031, respectively). This was probably because of degradation of deramciclane at lower pH of man’s stomach compared with that of the dog. Pentagastrin was probably unsuccessful in reducing gastric pH and thus no change in absorption was observed.
It is concluded that the absorption of deramciclane, and possibly other acid-labile drugs, cannot be predicted by use of the dog model.
Some 1-[(Benzofuran-2-yl)methy1]imidazoles as Inhibitors of 17α-Hydroxylase1:7, 20-lyase (P450 17) and Their Specificity Patterns
Authors: Bahshwan Saleh A , Owen Caroline P , Nicholls Paul J , Smith H John , Ahmadi Masoud 
Published: April 2011

Abstract
Four 1-[(benzofuran-2-yl)methyl]imidazoles (1–4) have been evaluated as in-vitro inhibitors of human testicular and bovine adrenal microsomal 17α-hydroxylase: 17,20-lyase (P450 17) as potential anti-prostatic agents. Their specificity towards other steroidogenic and liver enzymes has been compared with that of ketoconazole.
All four compounds were inhibitors of the testicular enzyme (2, IC50 (concentration resulting in 50% inhibition) 0.185 μm; 4, IC50 0.18 μM) but less potent than ketoconazole (IC50 0.03 μM). Towards bovine adrenal enzyme 2 and 4 were 35- and 31-fold more potent than ketoconazole (IC50 = 39.8 μM).
Compound 2 is a useful lead compound but although less potent than ketoconazole towards P450SCC and P45011β, but not P450C21, at the enhanced dose required for equivalent effects in-vivo on P450 17 it is likely that cortisol and aldosterone production will be affected to a greater extent than with ketoconazole.
Amitriptyline and Clomipramine Increase the Concentration of Administered L-Tryptophan in the Rat Brain
Authors: Eriksson Tomas , Wålinder Jan 
Published: April 2011

Abstract
The tricyclic antidepressant amitriptyline has been shown to reduce concentrations of large neutral amino acids (LNAA) in rat plasma. Compounds with that property might interact with such amino acids used as therapeutic agents with a central site of action by causing a change in the relationship between the administered LNAA and its endogenous LNAA competitors for carrier-mediated transport through the blood–brain barrier into the brain. This study was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan.
Intraperitoneal administration of L-tryptophan alone (100 mg kg−1) resulted in an increase in the concentration of tryptophan in the rat brain from 14 ±0.7 to 100 ± 4.3 nmol g−1 compared with rats given saline only. When rats were given tryptophan with amitriptyline (25 mg kg−1, i.p.) or clomipramine (25 mg kg−1, i.p.) brain concentrations of tryptophan were increased even further, to 150 ±4.5 and 157 ± 10.2 nmol g−1, respectively. Administration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LNAAs)] from 0.14±0.003 to 0.42±0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine the plasma tryptophan ratios were increased even further to 0.52 ±0.017 and 0.54 ±0.025, respectively. All these effects were statistically significant (P &lt; 0.001).
These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasma between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treatment of depression.
Activation of 11 β-Hydroxysteroid Dehydrogenase by Dehydroepiandrosterone Sulphate as an Anti-hypertensive Agent in Spontaneously Hypertensive Rats
Authors: Homma Masato , Onodera Toshiaki , Hirabatake Masaki , Oka Kitaro , Kanazawa Masao , Miwa Takashi , Hayashi Tohru 
Published: April 2011

Abstract
The anti-hypertensive properties of dehydroepiandrosterone sulphate (DHEAS) have been investigated by studying its effects on blood pressure, on serum concentrations of corticosterone and dehydrocorticosterone, and on 11 β-hydroxysteroid dehydrogenase (11 β-HSD) activity in spontaneously hypertensive rats (SHR).
SHR were given intraperitoneal injections of DHEAS (10 mg day−1 for 70 days) from six to 16 weeks of age. The blood pressure–time curve was significantly (P&lt;0.05) suppressed immediately after administration of DHEAS. There was no difference between the heart rates of control and DHEAS groups. Serum concentrations of corticosterone and dehydrocorticosterone in the DHEAS group were significantly (P &lt; 0.05) lower than those of the control group. The dehydrocorticosterone/corticosterone concentration ratio was, however, significantly (P &lt; 0.05) higher in the DHEAS group, suggesting that treatment with DHEAS enhanced the overall interconversion of corticosterone to dehydrocorticosterone. The activity of 11 β-HSD in specific organs of the DHEAS group was affected, characteristic changes being increases in the kidney (14–58%), decreases in the liver (11–27%) and no change in the testis. Direct addition of DHEAS to 11 β-HSD preparations from the kidneys of control SHR had the same effect as that observed in the in-vivo experiments.
The fall in serum corticosterone in the DHEAS group is considered to be related, at least partly, to increased activity of kidney 11 β-HSD. The inverse correlation of kidney 11 β-HSD activity with serum corticosterone and blood pressure (—r = 0.628, P &lt; 0.01, and —r = 0.478, P &lt; 0.05, respectively) suggest that DHEAS delayed the development of hypertension in SHR by selective promotion of kidney 11 β-HSD activity which in turn resulted in lower serum concentrations of corticosterone and its minimal aldosterone-like activity.
Anti-inflammatory Activity in Rats and Mice of Phenolic Acids Isolated from Scrophularia frutescens
Authors: Fernández M A , Sáenz M T , García M D 
Published: April 2011

Abstract
Different species of the Scrophularia genus (Scrophulariaceae) have been reported to have bacteriostatic and anti-inflammatory properties. In previous studies the anti-inflammatory and antibacterial activity of different extracts from Scrophularia frutescens were investigated and p-coumaric, caffeic, ferulic gentisic, protocatechuic, syringic and isovanillic acids were isolated and identified. In this work the anti-inflammatory activity of these compounds, administered orally, has been studied against carrageenan-induced rat paw oedema and, administered topically, against tetradecanoylphorbol acetate (TPA)-induced mouse ear oedema. The compounds’ myeloperoxidase activity in inflamed ear was also investigated.
Some of the phenolic acids were remarkably active in the TPA test (protocatechuic 71.59% inhibition, P &lt; 0.001; syringic 74.43%, P &lt; 0.001; ferulic 71.02% P &lt; 0.001) and all significantly inhibited mouse ear oedema. They were only moderately active, or were without activity, in the carrageenan test.
These results imply that the phenolic acids assayed are more effective topically than as oral anti-inflammatory agents and that their action is markedly influenced by the inhibition of neutrophil migration into inflamed tissue. This study has also enabled us to make some observations on the possible relationship between the chemical structure and antiinflammatory activity of the compounds assayed.
Development of an In-vitro Model to Study the Growth Characteristics of Staphylococcus epidermidis in Continuous Ambulatory Peritoneal Dialysis
Authors: Brant Janet A , Hanlon Geoffrey W , Denyer Stephen P 
Published: April 2011

Abstract
An in-vitro model of peritonitis in continuous ambulatory peritoneal dialysis (CAPD) has been developed which integrates the parameters of environmental gaseous tension, the changing biochemical profile of the dialysate, and the periodic challenge of fresh fluid.
Dwell times of 4 h during the day and 10 h at night were used to reflect the in-vivo situation. Biochemical analysis of dialysate within the model showed that the profiles for creatinine, glucose and protein approximated those found in patients. Staphylococcus epidermidis growing in synthetic dialysis effluent or pooled dialysis fluid were seen to adapt rapidly to the environment after an initial lag phase; a tendency to aggregate together increased over the 50-h period of operation.
In conclusion, the results presented here suggest that this in-vitro model creates an environment which is reflective of the in-vivo situation and therefore has potential for the study of peritonitis in CAPD.
Submicron Oil-in-water Emulsion Formulations for Mefloquine and Halofantrine: Effect of Electric-charge Inducers on Antimalarial Activity in Mice
Authors: Mbela T K M , Deharo E , Haemers A , Ludwig A 
Published: April 2011

Abstract
Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine.
The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg−1, respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg−1 for dicetylphosphate, 17 mg kg−1 for phosphatidylserine, 23 mg kg−1 for oleic acid and 27 mg kg−1 for stearylamine, again after subcutaneous administration.
This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.
The Role of the Iminium Bond in the Inhibition of Reverse Transcriptase by Quaternary Benzophenanthridines
Authors: Kerry Mark A , Duval Olivier , Waigh Roger D , Mackay Simon P 
Published: April 2011

Abstract
The quaternary benzo[c]phenanthridines fagaronine, nitidine and O-methylfagaronine have been reviewed as potential antitumour and antiviral agents. Their mode of action has not been established, but their ability to bind with DNA by intercalation is believed to be involved.
Of the three synthetic analogues of O-methylfagaronine which we have synthesized, methoxidine and ethoxidine are active against HIV-1 reverse transcriptase (IC50 values 2.8 μM and 2.4 μM respectively) whereas hydroxidine is inactive. One of the prerequisites for the enzyme inhibitory activity of this class of molecule is the presence of an iminium group-it is well known that a positive charge on a polyaromatic nucleus facilitates intercalative binding with DNA. Through UV spectrophotometric and modelling studies, we have shown that the iminium bond plays a more fundamental role in enzyme inhibition through its susceptibility to nucleophilic attack—the inactive analogue hydroxidine has a non-electrophilic iminium bond.
Consequently, we have demonstrated that iminium bond electrophilicity is a parameter which needs to be considered in ternary complex formation with reverse transcriptase.
Effect of Butylidenephthalide on Calcium Mobilization in Isolated Rat Aorta
Authors: Ko Wun-Chang , Charng Chuan-Yin , Sheu Joen-Rong , Tzeng Shu-Huey , Chen Chi-Ming 
Published: April 2011

Abstract
Butylidenephthalide (Bdph), an antispasmodic compound originally isolated from the rhizome of Ligusticum chuaxiong, has a selective anti-anginal effect without changing blood pressure. Experiments have been performed to determine the mechanism of this action.
Synthetic Z-butylidenephthalide concentration-dependently relaxed phenylephrine (1 μM)- or KC1 (60 mM)-induced precontractions of intact and denuded rat aorta rings. The relaxation induced by Bdph was endothelium-independent. Bdph (30–300 μM) concentration-dependently reduced cumulative phenylephrine- and KCl-induced contractions of intact rat aortic rings and non-competitively inhibited their log concentration-response curves. The pD2′ values of Bdph for phenylephrine- and KCl-induced contraction were 3.66 ± 0.13 (n = 8) and 3.71 ± 0.07 (n = 8), respectively, which were not significantly different from each other. Bdph also concentration-dependently reduced cumulative Ca2+-induced contractions of intact rat aortic rings in high-KCl (60 mM) Ca2+-free physiological salt solution and non-competitively inhibited its log concentration—response curve. The pD2′ value of Bdph for the Ca2+-induced contractions was 3.21±0.01 (n = 7) which was significantly different from the pD2′ value obtained from the cumulative KCl-induced contractions.
These results suggest that Bdph inhibits calcium release from calcium stores more selectively than calcium influx from extracellular space via voltage-dependent calcium channels. The inhibition by Bdph of calcium release from KCl-sensitive calcium stores might be similar to its inhibition of calcium release from phenylephrine-sensitive calcium stores. However, because phenylephrine generates inositol-1,4,5-trisphosphate (IP3) whereas KCl does not, the inhibitory effect of Bdph might not be related to IP3 production.
Effects of Tamoxifen on Striatal Dopamine and 5-Hydroxytryptamine Release in Freely Moving Male Rats: An In-vivo Microdialysis Investigation
Authors: Chaurasia Chandra S , Chen Chu-En , Rubin Jason , Dewey Stephen L 
Published: April 2011

Abstract
Recent studies indicating interaction of oestrogens with central cholinergic, dopaminergic and 5-HTergic systems have led to the assumption of a protective role of oestrogens in certain neurodegenerative disorders. The non-steroidal drug tamoxifen, a mixed oestrogen agonist—antagonist, has been shown to modulate central nervous system functions in the corpus striatum. In this study we used a microdialysis technique to examine the effects of tamoxifen upon the striatal dopaminergic and 5-HTergic systems in intact freely moving male rats.
The extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were measured after intraperitoneal administration of either the control or tamoxifen, and were compared with their corresponding baseline levels. Significant 25–35% increases in the baseline levels of dopamine and 3,4-dihydroxyphenylacetic acid were observed after the highest doses of tamoxifen (1.5mgkg−1 and 3.Omgkg−1, respectively), whereas the lowest dose of tamoxifen (0.3mgkg−1) elevated dopamine and 3,4-dihydroxyphenylacetic acid levels by a detectable 15% of the basal. In addition, the ratio of 3,4-dihydroxyphenylacetic acid-to-dopamine remained unchanged in comparison with that of the pretreatment levels. Whereas no change in the striatal 5-hydroxyindoleacetic acid concentrations was seen with the lowest and highest dose regimen, the intermediate dose elicited a moderate increase (20%) in basal 5-hydroxyindoleacetic acid levels.
The pharmacological relevance of the effects of tamoxifen on the dopaminergic and 5-HTergic systems, as a prelude to the development of non-steroidal oestrogenic compounds in reducing the risk of neurodegenerative disorders such as Alzheimer’s disease, is discussed.
Solution-structure of a Peptide Designed to Mimic the C-terminal Hexapeptide of Endothelin
Authors: van der Walle C F , Bansal S , Barlow D J 
Published: April 2011

Abstract
The peptide: Ac-cyclo(Cys-His-Leu-Asp-Cys)-Ile-Trp-OH, has been designed by computer-aided molecular-modelling techniques to mimic the proposed α-helical conformation of the C-terminal hexapeptide of endothelin.
Two-dimensional proton nuclear magnetic resonance spectra were acquired for the peptide dissolved in d6-DMSO or D2O-H2O and the distance and angle constraints incorporated into simulated annealing experiments. Conformers generated from the D2O-H2O data superposed on the corresponding main-chain atoms in the crystal structure of endothelin 1 and the solution structure of BQ-123 with root mean square co-ordinate differences of 0·9 Å and 0·77 Å, respectively. The peptide did not elicit antagonism of endothelin-induced in-vitro contractions of rabbit aorta (endothelin A receptor) or rabbit bronchus (endothelin B receptor) preparations.
Because the peptide can adopt a conformer which closely matches the equivalent residues in the endothelin 1 crystal structure and in BQ-123, we suggest BQ-123 does not necessarily mimic the endothelin C-terminal region to achieve its antagonism, and that a helical conformation of the endothelin C-terminal hexapeptide does not favour its interaction at the endothelin B receptor.