bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Nifedipine Metabolism in Dogs by Erythromycin: Difference between the Gut Wall and the Liver
Authors: Tsuruta Satoshi , Nakamura Kazumi , Arimori Kazuhiko , Nakano Masahiro 
Published: April 2011

Abstract
The purpose of this study was to evaluate possible interaction of nifedipine with erythromycin or rokitamycin in the intestinal mucosa. Male beagle dogs were orally administered nifedipine (10 mg), with or without oral pre-medication with erythromycin (300 mg), and 300 mg erythromycin or rokitamycin twice a day for 3 days. The experiments were of randomized cross-over design with a two-week wash-out period between dosing regimens.
Erythromycin pre-medication for 3 days resulted in a significant increase in the area under the serum nifedipine concentration-time curve (AUC), whereas the curve for one nifedipine metabolite (M-2) decreased significantly. When the effects of erythromycin on the metabolism of nifedipine were studied using dog liver microsomes it was found that erythromycin significantly inhibited formation of M-2 but not of the metabolite M-1. These results indicate that formation of M-2 from M-1 in the liver might be reduced by erythromycin premedication. To avoid possible metabolism in the gut, the dogs were then administered 8 mg nifedipine into the peritoneal cavity, with or without multiple dose pre-treatment with erythromycin for 3 days. After intraperitoneal administration of nifedipine, the maximum concentration (Cmax) of nifedipine increased significantly.
After pre-administration of erythromycin the relative bioavailability of nifedipine after oral administration was increased compared with injection into the peritoneal cavity. In-vitro study using rat intestinal microsomes and the in-vivo rat intestinal loop technique also showed that pre-administration of erythromycin inhibits nifedipine metabolism in the small intestine.
Comparison of the Effects of Histamine and Nα-Methylhistamine on Neuronal Function in the Guinea-pig Oesophagus and Ileum
Authors: Hemedah Maggie , Mitchelson Frederick 
Published: April 2011

Abstract
The effects of histamine and Nα-methylhistamine, two components of gastric juice, on vagal and transmural stimulation of the guinea-pig isolated oesophagus were compared with their effects on cholinergic and on non-adrenergic-non-cholinergic (NANC) neuronal responses in the isolated ileum, both tissues having been pretreated with mepyramine (1 μm).
Histamine (≤10 μm) and Nα-methylhistamine (≤1 μm) had no significant effect on either vagal or transmural stimulation in the oesophagus. Substance P, which produces a contraction by activation of cholinergic nerves in the oesophagus also was unaffected by histamine. In contrast, the agonists inhibited contractions produced by cholinergic nerve stimulation in the ileum; the inhibition produced by histamine (10 μm) was up to 73 ± 5%, that by Nα-methylhistamine (1 μm), 48 ± 5%. Histamine also inhibited responses to stimulation of NANC neurons by up to 37 ± 14%. The effects of histamine and Nα-methylhistamine in the ileum were inhibited by clobenpropit (01 μm).
These findings suggest that histamine and Nα-methylhistamine have no role in the modulation of neuronal function in the oesophagus, in contrast with their effect in the ileum.
Stability of Artemisinin in Aqueous Environments: Impact on its Cytotoxic Action to Ehrlich Ascites Tumour Cells
Authors: Beekman Aäron C , Woerdenbag Herman J , Van Uden Wim , Pras Niesko , Konings Antonius W T , Wikström Håkan V 
Published: April 2011

Abstract
We have recently shown artemisinin to be cytotoxic against Ehrlich ascites tumour cells. The aim of this study was to investigate the stability of this compound in the aqueous environment of the in-vitro Ehrlich ascites tumour cell system (RPMI 1640 cell culture medium supplemented with 10% foetal bovine serum (RPMI/FBS) with reference to its cytotoxic action.
Literature data show that artemisinin can react with Fe2+ yielding reactive intermediates leaving artemisinin G as a major end-product. The current study showed that only excess addition of Fe2+ to artemisinin in distilled water, phosphate-buffered saline (PBS) and RPMI/FBS and incubation for 24 h led to degradation of artemisinin and yielded artemisinin G. If Fe2+ was not added results from HPLC analysis were indicative of complete recovery of artemisinin from distilled water and RPMI/FBS, with or without cells, at 37°C for at least 24 h. In addition, incubation of artemisinin in RPMI/FBS with or without cells at 37°C for 24 h before cytotoxicity assay did not change its cytotoxic action.
On the basis of these results, we suggest that cytotoxicity to tumour cells was caused by unchanged artemisinin. This is not so for the antimalarial activity of artemisinin and derivatives, for which the presence of a pool of (haem) Fe2+ is a prerequisite resulting in free radicals or electrophilic intermediates or both.
Human Jejunal Effective Permeability and Its Correlation with Preclinical Drug Absorption Models
Authors: LennernÄs Hans 
Published: April 2011

Abstract
This review focuses on intestinal permeability measurements in humans and various aspects of in-vivo transport mechanisms. In addition, comparisons of human data with preclinical models and the blood-brain barrier is discussed.
The regional human jejunal perfusion technique has been validated by several crucial points. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. We have also shown that it is possible to determine the effective permeability (Peff) for carrier-mediated transported compounds, and to classify them according to the proposed Biopharmaceutical Classification System (BCS). Furthermore, it is possible to predict human in-vivo permeability using precuneal permeability models, such as in-situ perfusion of rat jejunum, the Caco-2 model and excized intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. It is also suggested that it is possible to roughly estimate the permeability of the blood-brain barrier using measurements of intestinal permeability, even if the quantitative role of efflux of P-glycoprotein(s) in-vivo still remains to be clarified.
Finally, the data obtained in-vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in-vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It is also important to study the effect of anti-transport mechanisms, such as efflux by P-glycoprotein(s), and gut wall metabolism, for example CYP 3A4, on the bioavailabaility.
Characterization of the Block Structure and Molecular Weight of Sodium Alginates
Authors: Johnson Fiona A , Craig Duncan Q M , Mercer Amanda D 
Published: April 2011

Abstract
Sodium alginates are widely used within the pharmaceutical sciences, yet the molecular characteristics of these materials are frequently not stated. In this study, a range of characterization techniques is applied to five sodium alginate samples and the data compared, both between techniques and with the information obtained from the manufacturer.
The mannuronic acid to guluronic acid (MG) ratio and the distribution of uronic acid residues of five sodium alginate samples have been measured using circular dichroism and NMR, with circular dichroism yielding MG ratios between 42.1 and 63.6%, depending on the grade of alginate used. The MG ratios obtained from NMR studies were in broad agreement with these values, and the technique also yielded information on the distribution of uronic acid residues within each batch; this was again found to vary considerably (NG &gt; 1 values ranging from 6.9 to 17.5). It was noted that samples with similar MG ratios could have markedly different chain-distribution characteristics. The uronic acid ratio ranges obtained from the manufacturers were found to be in good agreement with those found experimentally. Intrinsic viscosity measurements were used to compare the molecular weights of the samples; values between approximately 12000 and 180000 were obtained for the different batches.
The study has enabled comparison of different methods for characterization of sodium alginate samples, highlighting their relative merits and the possible protocols that might be adopted. A critical discussion is given of the individual and combined use of these techniques and the relevance of such studies to the rational design and quality control of alginate-based pharmaceutical systems.
Oral Delivery and Fate of Poly(lactic acid) Microsphere-encapsulated Interferon in Rats
Authors: Eyles J E , Alpar H O , Conway B R , Keswick M 
Published: April 2011

Abstract
In the light of previous findings which suggest that particulate material can be absorbed and thence systemically disseminated from the gastrointestinal tract, we have investigated the oral uptake and distribution of soluble and microsphere-encapsulated radiolabelled interferon-γ.
For trace-loaded (0.01% w/w interferon) microspheres, a quite different distribution of radioactivity was observed in-vivo 15 and 240 min after oral administration, in comparison with the control group which received equivalent doses of unencapsulated interferon-γ. Thyroid gland activity in control animals killed at these times was significantly higher than that detected in those rodents receiving trace amounts of microencapsulated interferon-γ (P ≤ 0.05). For poly(l-lactide) particles with higher interferon loadings (0.97% w/w interferon-γ) the distinction between the two experimental groups was less significant. During incubation in-vitro, the trace-loaded particles released a significantly lower percentage of interferon-γ in comparison with 0.97% w/w loaded microspheres (P ≤ 1).
Bio-distribution data from rats treated orally with trace amounts of unencapsulated and microencapsulated interferon-γ leads us to the tentative conclusion that microencapsulation of proteins markedly affects oral uptake, and possibly post-absorption pharmacokinetic parameters also.
Effect of the Size of Liposomes on the Transfer and Uptake of Carboxyfluorescein by the Perfused Human Term Placenta
Authors: Bajoria Rekha , Contractor Soli F 
Published: April 2011

Abstract
The effect of the size of liposomes on the uptake and transfer of the low molecular-weight, hydrophilic and polar molecule carboxyfluorescein has been determined across the perfused human term placenta.
Carboxyfluorescein-encapsulated neutral liposomes of three different sizes were prepared from equimolar concentrations of lecithin and cholesterol. Size distribution, encapsulation efficiency and stability of liposomes in blood-based media were determined. The concentration of carboxyfluorescein was measured spectro-photometrically. The transplacental transfer and placental uptake of free carboxyfluorescein (control data) were respectively 1.9 ±0.2 and 5.0 ± 0.7% of initial dose. The placental uptake and foetal concentration of carboxyfluorescein were significantly increased by small liposomes (P &lt; 0.05), and reduced by large (0.82 ± 0.13%; P &lt; 0.05) and multilamellar liposomes (0.32 ± 0.11%). There was a negative correlation between liposome size and transplacental transfer (y = −0.53 + 0.9x; r = 0.96; P &lt; 0.001; n = 24) and placental uptake of carboxyfluorescein (y = −5.9 + 6.5x; r = 0.84; P &lt; 0.001; n = 24).
The study indicates that placental uptake and transfer rate of liposomal carboxyfluorescein were dependant upon the size of liposomes.
Cholinergic Modulation of Electrogenic Ion Transport in Different Regions of the Rat Small Intestine
Authors: Przyborski S A , Levin R J 
Published: April 2011

Abstract
Acetylcholine acting via muscarinic receptors located in the intestinal mucosa controls ion and fluid transport. This study examined the pathway(s) by which cholinergic receptors mediate secretion in rat isolated duodenum, jejunum and ileum using the short-circuit current (Isc) as an index of electrogenic Cl− secretion.
Carbachol and bethanechol induced electrogenic Cl− transport which was insensitive to the neural blocker tetrodotoxin, indicating their direct action on the enterocytes. Functional characterization of electrogenic secretion activated via muscarinic receptors on jejunal and ileal enterocytes was achieved by use of selective muscarinic antagonists in the presence of tetrodotoxin. In both regions the rank order of potency of these compounds (atropine &gt; 4-diphenylacetoxy-N-piperidine methiodide (4-DAMP) &gt; hexahydro-sila-difenidol (HHSiD) &gt; pirenzepine &gt; methoctramine) indicated the M3 receptor subtype. Secretion activated by the muscarinic agonist 4-[[(3-chlorophenyl)amino]carbonyl]-N,N,N-trimethyl-2-butyn-1-ammonium chloride (McN-A-343) was sensitive to tetrodotoxin and pirenzepine but not to the ganglionic blocker, hexamethonium, indicating the M1 receptor subtype on post ganglionic neurons. Regional differences for bethanechol-activated secretion showed an increasing gradient in secretory capacity (Isc max) in a proximal-to-distal direction along the small intestine. Responses to McN-A-343 also showed regional differences but these were unlike those of bethanechol.
These results show that cholinomimetic-induced electrogenic Cl− secretion in rat isolated small intestine appears to be mediated by two dissimilar populations of muscarinic receptor: M3 muscarinic receptors positioned on enterocytes and M1 muscarinic receptors sited on submucosal neurons.
The Ligand-binding Site of Buspirone Analogues at the 5-HT1A Receptor
Authors: Sylte Ingebrigt , Chilmonczyk Zdzislaw , Dahl Svein G , Cybulski Jacek , Edvardsen Øyvind 
Published: April 2011

Abstract
A three-dimensional model of the 5-HT1A receptor in man was constructed by molecular-modelling techniques and used to study the molecular interactions of a series of buspirone analogues with the 5-HT1A receptor by molecular-mechanical-energy minimization and molecular-dynamics simulations.
The receptor has seven trans-membrane α helices (TMHs) organized according to the electron-density-projection map of visual rhodopsin, and includes all loops between TMHs and the N- and C-terminal parts. The best fit between the buspirone analogues and the receptor model was obtained with the quinolinyl part of the ligand molecules interacting with amino acids in TMH6, the imide group interacting with amino acids in TMH2, TMH3 and TMH7, and the carbonyl groups hydrogen-bonded with Ser86 and Ser393. The ligand-binding rank order deduced from the experimentally determined inhibition constant was reproduced by calculation of receptor-binding energies of the buspirone analogues.
The models suggest that steric hindrance and repulsive forces between the receptor and the imide group of the buspirone analogues are the most important determinants of ligand-binding affinity for discriminating between these ligands.
Indole Alkaloids from Sickingia williamsii Reduce the In-vitro Effects of Morphine Withdrawal in the Guinea-pig
Authors: Capasso A , Aquino R , Garofalo L , de Simone F , Sorrentino L 
Published: April 2011

Abstract
The effect of indole alkaloids from Sickingia williamsii Standi. (Rubiaceae) on the effects of morphine withdrawal have been examined in-vitro.
All the indole alkaloids isolated from S. williamsii (10−4, 5 ×10−5 and 10−5 m) significantly and in a concentration-dependent manner reduced the effects of morphine withdrawal on the guinea-pig ileum.
The results suggest that these alkaloids might be potential anti-addictive agents.
Interaction of Local Anaesthetics with Histamine H1 Receptors in Guinea-pig Ileum
Authors: Horio Shuhei , Nagare Toshitaka , Ishida Yukio , Moritoki Hideki 
Published: April 2011

Abstract
The interaction of amine local anaesthetics and related compounds with histamine H1 receptors was investigated in guinea-pig ileal longitudinal muscle.
Quinacrine, chloroquine, tetracaine and procaine inhibited [3H]mepyramine binding to solubilized membrane from ileal muscle with pKi values of 5.27 ± 0.11, 5.66 ± 0.01, 4.28 ± 0.08 and 3.97 ± 0.11, respectively. The pKB values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 549 ± 0.11, 6.14 ± 0.09, 4.86 ± 0.06 and 4.58 ± 0·06, respectively, in reasonable agreement with the pKi values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H1 receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization.
The results suggested that most of these local anaesthetics interacted competitively at histamine H1 receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allo-sterically and inhibited desensitization through a separate action.
Use of Microdialysis for In-vivo Monitoring of Hydroxyl Free-radical Generation in the Rat
Authors: Obata Toshio 
Published: April 2011

Abstract
Free-radicals are reported to cause the tissue-damage associated with some toxins and diseases, yet there is no suitable method for routine in-vivo monitoring of these species. This paper introduces an in-vivo microdialysis technique in which the hydroxyl radical reacts with salicylate to generate dihydroxybenzoic acids (DHBA) which are measured by HPLC with electrochemical detection.
When pargyline, a monoamine oxidase inhibitor, was infused into rat brain, the levels of DHBA increased markedly. When noradrenaline was administered to animals pre-treated with pargyline, DHBA levels increased markedly compared with the group treated with noradrenaline only. When the heart was subjected to 15-min regional ischaemia by occlusion of the left anterior descending coronary artery, levels of DHBA in heart dialysate were unchanged. Electrical stimulation of the stellate ganglion resulted in marked elevation of levels of DHBA the myocardial dialysate. Infusion of Fe2+ into rat liver resulted in increased formation of DHBA. When the intestine was rendered ischaemic for 10, 20 and 30 min, the highest DHBA level was obtained after 10-min ischaemia and the lowest after 30 min.
These results confirm that free-radical production might make a major contribution at certain stages in the progression of the injury.
Synthesis and Evaluation of Brain-targeted Chemical Delivery Systems for the Neurotrophomodulator 4-Methylcatechol
Authors: Kourounakis Angeliki , Bodor Nicholas , Simpkins James 
Published: April 2011

Abstract
Since various 4-alkylcatechols stimulate nerve growth factor (NGF) biosynthesis both in-vitro and in-vivo, delivery of these agents to the brain may provide beneficial effect for the treatment of neurodegenerative diseases such as Alzheimer's.
Several dihydropyridine-pyridinium salt type redox chemical delivery systems (CDS) of 4-methylcatechol (4-methylcatechol) were prepared as potential brain selective targetry forms for 4-methylcatechol. After preliminary evaluation by in-vitro stability studies in various buffer solutions and biological media, a selected CDS was further investigated in the rat to determine its in-vivo distribution. Selective and sustained delivery of the compound of interest to the rat brain was achieved. Furthermore, the NGF stimulatory activity in the rat brain after peripheral administration of the selected CDS was evaluated by measuring the levels of pre-pro-NGF mRNA in the rat hippocampus and frontal cortex, by dot blot hybridization and analysis.
Results showed the peripheral administration of the CDS to achieve a 1.7-fold increase in NGF mRNA compared to control in the rat hippocampus, and an approximately 1.4-fold increase in the frontal cortex.
Pharmacological Studies of 1-(p-Chlorophenyl)propanol and 2-(1-Hydroxy-3-butenyl)phenol: Two New Non-narcotic Analgesics Designed by Molecular Connectivity
Authors: GarcíA-March F J , García-Domenech R , Gálvez J , Antón-Fos G M , de Julián-Ortiz J V , Giner-Pons R , Recio-Iglesias M C 
Published: April 2011

Abstract
Molecular topology has been applied to the design of new analgesic drugs. Linear discriminant analysis and connectivity functions were used to design two potentially suitable drugs which were synthesized and tested for analgesic properties by the acetic acid-induced abdominal constriction test in mice and the tail-flick test in rats.
In mice, the compound 1-(p-chlorophenyl)propanol showed higher analgesic activity, both intraperitoneally and orally, than acetylsalicylic acid. 2-(1-Hydroxy-3-butenyl)phenol exhibited a lesser protective effect (70% of that shown by acetylsalicylic acid). In rats, acetylsalicylic acid gave the greatest protection against pain when administered intraperitoneally, while 1-(p-chlorophenyl)propanol was the most active orally. The 2-(1-hydroxy-3-butenyl)phenol, both intraperitoneally and orally, snowed the least protective effect.
These results demonstrated the peripheral analgesic properties of the selected compounds, thus confirming the validity of the molecular design method.
A Submicron Lipid Emulsion Coated with Amphipathic Polyethylene Glycol for Parenteral Administration of Paclitaxel (Taxol)
Authors: Lundberg Bo B 
Published: April 2011

Abstract
Paclitaxel is a promising anticancer agent with poor solubility in water and requires a suitable formulation for intravenous administration. Presently paclitaxel is formulated for clinical use in ethanol and Cremophor EL (Diluent 12), a solvent system associated with severe adverse effects. In this study paclitaxel was entrapped in lipid emulsion droplets with triolein as oil core and dipalmitoyl phosphatidylcholine as the principal emulsifier. The emulsion was further stabilized with polysorbate 80 and polyethylene glycol-dipalmitoyl phosphatidy-lethanolamine.
The drug-emulsion droplets (diameter about 40 nm) were physically and chemically stable during several months at 4°C. Lyophilized preparations in 5% glucose were completely restored by distilled water. Studies of the integrity of the drug-emulsion showed a release of the drug from emulsion globules and surface transfer was found to be the major mechanism for cellular uptake. The in-vitro antiproliferative activity of paclitaxel against T-47D cells was retained by the drug-emulsion with an ID50 value of 7 nM compared to 10 and 35 nM for paclitaxel in liposomes and Diluent 12, respectively.
Long-circulating submicron lipid emulsions may prove useful, not only for replacement of the more toxic Cremophor EL vehicle, but also by improving the distribution of the drug to the tumour.