bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and Validation of a Pig Model for Colon-specific Drug Delivery
Authors: Gardner Naomi , Haresign Will , Spiller Robin , Farraj Nidal , Wiseman Julian , Norbury Heather , Illum Lisbeth 
Published: April 2011

Abstract
The purpose of this investigation was to develop a pig model for colonic drug delivery and to validate the model by determining whether the physiology of the pig colon had been significantly altered after the surgical implantation of a gut cannula into the terminal ileum of the pig.
A fistula was created in the terminal ileum of the pig, and a cannula fitted for the purpose of directly administering drug formulations to a point just anterior to the ileocaeco-colonic valve of the gastrointestinal tract. The cephalic vein of the pig was also cannulated to enable continued blood sampling.
Sulphasalazine was used as the model drug for the validation study. In the intact colon, sulphasalazine is metabolized by the gut microflora to sulphapyridine which is then absorbed. Sulphasalazine was administered orally to non-fistulated and fistulated pigs and then ileally, via the gut cannula, to fistulated pigs. Absorption of sulphapyridine was monitored by HPLC analysis of plasma samples. There was no significant difference in the absorption obtained for the three groups. Thus it is demonstrated that the colon physiology had not been altered.
The colonic pig model is ideal for studying factors affecting the colonic absorption of drugs and as a means for developing drug delivery systems with improved absorption properties.
Synergistic Inhibition of Human Polymorphonuclear Function by Prostaglandin E1 and Linsidomine
Authors: Gladis-Villanueva Mar , Schrör Karsten 
Published: April 2011

Abstract
Polymorphonuclear cells (PMN) are the dominating inflammatory cell population in acute tissue injury and contribute to host-defence mechanisms by formation and release of chemical mediators. The aim of the present study was to investigate whether chemoattractant-induced PMN stimulation can be synergistically antagonized by vasodilatory prostaglandins and nitric oxide (NO), both being formed by the vasculature in inflamed areas. PGE1 (10 nM−10 μM) inhibited concentration-dependently formyl-methionyl-leucyl-phenylalanine (fMLP)-induced β-glucuronidase and oxygen radical (O2) release from human PMN. The NO donor linsidomine (100 μM) was ineffective, but significantly enhanced PGE1 effects on oxygen radical generation and enzyme release. The non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM) potentiated PGE1 effects on all parameters measured. The combination linsidomine (100 μM) plus IBMX (0.5 mM) did not additionally reduce β-glucuronidase release, but abolished fMLP-stimulated O2 generation. There was a stimulation of cAMP formation by PGE1 but not by linsidomine, both in the absence and presence of IBMX.
It is concluded that the effects of linsidomine on PMN function and its synergism with PGE1 are not tightly correlated with total cAMP accumulation. Alternatively, the inhibition of O2 generation by linsidomine may be related to its ability to modulate the activation of the NADPH oxidase system or to scavenge free oxygen radicals.
Rat Protein Binding and Cerebral Phospholipid Affinity of the H3-receptor Antagonist Thioperamide
Authors: Plazzi P V , Mor M , Silva C , Bordi F , Morini G , Crivori P , Caretta A 
Published: April 2011

Abstract
The binding of thioperamide, a known H3-receptor antagonist, to rat plasma proteins and its affinity for rat cerebral phospholipids are investigated.
Thioperamide is strongly bound to plasma proteins (95−80% at plasma concentrations of 3.5−400 μg mL−1), and its binding can be resolved into two components: a high-affinity, saturable component and a non-specific component. The drug has a high affinity for cerebral phospholipids, with a partition coefficient of approximately 100 (log K = 2.06 ± 0.14), which should promote brain penetration and accumulation.
Protein binding and cerebral phospholipid affinity can suggest the explanation of some differences reported in the literature on thioperamide distribution data: at low plasma concentrations of the drug, its protein binding (95% at 3.5 μg mL−1) can prevent brain accumulation, while at higher concentrations the free plasma fraction suddenly increases (&gt; 10% at 18 μg mL−1) and it allows passive distribution to lipophilic tissues such as brain tissue.
Mefloquine Effect on Disposition of Halofantrine in the Isolated Perfused Rat Liver
Authors: Leo Kathleen U , Wesche David L , Marino Mark T , Brewer Thomas G 
Published: April 2011

Abstract
Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine.
Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean ± s.d.) were: volume of distribution (Vd), 7.53 ± 1.45 mL (g liver)−1; clearance (CL), 0.11 ± 0.07 mL min−1 (g liver)−1; initial distribution half-life (initial t1/2), 14.62 ± 2.38 min; terminal half-life (terminal t1/2), 138.7 ± 178.8 min; AUC 606 ± 194 mg mL−1 min−1 (g liver)−1; elimination rate constant (Ke), 0.0135 ± 0.012 min−1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, Ke, initial and terminal t1/2 (P &gt; 0.05). A single dose, short term (4−6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefioquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P &lt; 005) and biliary clearance (P &lt; 005) of halofantrine in mefioquine-pretreated livers.
These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.
The Podiatric Treatment of Hallux Abducto Valgus and Its Associated Condition, Bunion, with Tagetes patula
Authors: Khan M Taufiq 
Published: April 2011

Abstract
To assess the effectiveness of marigold therapy using Tagetes patula preparations, a double-blind placebo-controlled trial was designed to be carried out over a period of eight weeks. Sixty patients were entered in the trial. Twenty patients with bilateral hallux abducto valgus and its associated condition, bunion, were randomly selected from 37 subjects for group A. For group B, 40 patients with unilateral hallux abducto valgus and bunion were randomly selected from 69 subjects and subdivided into groups Ba and Bb. Patients with ulcerated conditions, those on medication and those who had undergone surgery for the condition were excluded.
The results obtained were highly significant (P &lt; 0.001), suggesting that T. patula preparations, plus protective pad, were effective in reducing the width of the lesion and level of pain of hallux abducto valgus.
Clinical Pharmacokinetics of Ondansetron. A Review
Authors: Simpson Karen H , Hicks Fiona M 
Published: April 2011

Abstract
5−HT3 receptors are ubiquitous in the enteric, sympathetic, parasympathetic and sensory nervous systems and in the central nervous system (CNS) (Kilpatrick et al 1990). In man 5−HT3 receptors are mainly situated on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferents (Reynolds et al 1989), and the area postrema of the brain stem, which forms the chemoreceptor trigger zone. Ondansetron is a selective antagonist at 5−HT3 receptors. It is 100 times more potent than metoclopramide at this site (Tyers 1992). It shows limited binding to other receptors and has a wide therapeutic window. Ondansetron is a useful antiemetic which probably has both central and peripheral actions in patients undergoing radiotherapy, cytotoxic chemotherapy or general anaesthesia (Naylor & Rudd 1992). This paper reviews the pharmacokinetics of ondansetron in health and disease to provide information for clinicians; it might alter prescribing and alert them to possible drug interactions.
Solidification Studies of Polyethylene Glycols, Gelucire 44/14 or their Dispersions with Triamterene or Temazepam
Authors: Dordunoo Stephen K , Ford James L , Rubinstein Michael H 
Published: April 2011

Abstract
The solidification of polyethylene glycols (PEG 1500, PEG 2000, PEG 4000, PEG 6000), gelucire 44/14 or their dispersions containing triamterene or temazepam were studied to assess the feasibility of using these dispersions to liquid-fill hard gelatin capsules.
Solidification from melts, investigated by differential scanning calorimetry using cooling cycles, showed a tendency of the drugs, carriers or their dispersions to supercool. The degree of supercooling depended on the rate of cooling, the drug content and, for the PEGs, on the molecular weight. PEG 1500 and PEG 2000 gave one morphological form, irrespective of cooling rate; PEG 4000 and PEG 6000 solidified into at least two forms, depending on the cooling rate. Incorporation of drugs affected the morphology of the PEGs during solidification. The rate of crystal growth was, furthermore, influenced by the fusion temperature, molecular weight and the degree of supercooling. The degree of crystallinity, as measured by the enthalpies of solidification, decreased with increasing cooling rate.
The results show that reducing the rate of solidification could lead to incomplete solidification, giving products that are liable to change on storage.
Physicochemical Characterization of Bisphosphonic Carboxyfluorescein for Osteotropic Drug Delivery
Authors: Fujisaki Jiro , Tokunaga Yuji , Takahashi Toshiya , Murata Saburo , Shimojo Fumio , Hata Takehisa 
Published: April 2011

Abstract
Disodium (fluorescein-6−carbonyloxy)acetoaminomethylene bisphosphonate (CF-BP), a prodrug of 6−carboxy-fluorescein, is efficiently absorbed by the skeleton where it hydrolyses to carboxyfluorescein. An osteotropic drug-delivery system based on this bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. In this study the physicochemical properties of the prodrug have been characterized by investigating the affinity of CF-BP for hydroxyapatite and the hydrolysis of the compound to carboxyfluorescein.
In the binding study, CF-BP bound very rapidly to hydroxyapatite without degradation and carboxyfluorescein was subsequently gradually released by hydrolysis of bound CF-BP. Hydrolysis of CF-BP in buffer solutions followed pseudo-first-order kinetics, and quantitative regeneration of carboxyfluorescein was observed. In addition, regeneration of carboxyfluorescein from CF-BP was accelerated in the presence of fresh rat plasma.
These results suggest that CF-BP has the physicochemical properties required for site-specific and controlled delivery of carboxyfluorescein to bones.
An In-vitro Study of the Effect of Hydrocolloid Patch Occlusion on the Penetration of Triamcinolone Acetonide through Skin in Man
Authors: Ladenheim D , Martin G P , Marriott C , Hollingsbee D A , Brown M B 
Published: April 2011

Abstract
The aim of this study was to evaluate the effect of occlusion using hydrocolloid-containing patches on in-vitro triamcinolone acetonide (TACA) penetration of the epidermis while monitoring the uptake of water by the patches as a result of transepidermal water loss.
The hydrocolloid patches were a laminate of a pressure-sensitive hydrophobic adhesive (containing a dispersion of 39% of either pectin or carmellose sodium) and a polyethylene film. The diffusion of a representative corticosteroid (TACA) through isolated epidermal sheet was shown to depend on the site from which the skin was removed. The two patch-types exhibited markedly different hydration rates when applied to the membranes. For example, after 96 h the carmellose sodium patch showed ten times the weight increase of the pectin patch. Epidermal diffusion rates were, however, similar, both showing a 3−4−fold enhancement over unoccluded conditions.
The increase in TACA diffusion with the patches can be explained by the increase in skin hydration that occurs during occlusion. Despite the large differences in transepidermal water transfer through the epidermal membranes with the two types of hydrocolloid patch, however, this level of stratum corneum hydration was apparently similar. As the rate of diffusion was also independent of hydrocolloid patch component, it seems possible that the hydrophobic component of the patch matrix may also influence the level of skin hydration and consequent drug diffusion.
Amelioration of Disordered Hepatic Protein Synthesis by the Deleted Form of Hepatocyte Growth Factor in Models of Liver Failure in Rats
Authors: Masunaga Hiroaki , Fujise Nobuaki , Shiota Akira , Yamashita Yasushi , Yasuda Hiroshi , Higashio Kanji 
Published: April 2011

Abstract
Because the liver plays an important role in protein synthesis and cholesterol metabolism and reductions in these functions are observed in almost all hepatic disorders, the effects of the deleted form of hepatocyte growth factor (dHGF) on disordered hepatic protein synthesis were studied in various liver-injured rat models using Wistar male rats.
In the 70% hepatectomized rats, plasma clotting time was prolonged and the serum level of total protein and the liver protein content were decreased. The treatment of the animals with dHGF (100−500 μg kg−1, i.v., twice daily) ameliorated these parameters at 48 or 72 h. The administration of carbon tetrachloride or D-galactosamine to hepatectomized rats induced a marked prolongation of plasma clotting time and hypoproteinaemia. In the animals treated with dHGF (500 μg kg−1, i.v., twice daily) these parameters were rapidly reversed compared with those of control groups. In a hepatocellular necrosis model induced by dimethylnitrosamine, the plasma clotting time was extremely prolonged, and liver protein content, serum total protein, albumin, HDL-cholesterol (as an index of lipoprotein) and plasma lecithin-cholesterol acyltransferase activity severely reduced. In this severely injured model, dHGF (5−500 μg kg−1, i.v., twice daily for 28 days) dose-dependently prevented the loss of liver protein content and improved the disordered plasma coagulability and serum protein levels.
These results suggest that dHGF is useful for ameliorating the disorders in hepatic functions such as protein synthesis.
Blood-brain-barrier Transport of Lipid Microspheres Containing Clinprost, a Prostaglandin I2 Analogue
Authors: Minagawa Toshiya , Sakanaka Kohji , Inaba Shin-Ichi , Sai Yoshimichi , Tamai Ikumi , Suwa Toshio , Tsuji Akira 
Published: April 2011

Abstract
Because the permeability of the blood-brain barrier to lipid microspheres (LMs) has not hitherto been demonstrated, blood-brain-barrier permeability to LM containing the prostaglandin I2 analogue clinprost has been evaluated for an in-vitro system of primary cultured monolayers of bovine brain capillary endothelial cells (BCECs), by a capillary depletion study in rats and by an in-situ brain perfusion study in normal and 4-vessel-occluded fore brain ischaemic rats.
Although energy-dependency was not observed in [3H]clinprost uptake by BCECs, in accordance with results for simple diffusional transport, uptake of [3H]clinprost contained in lipid microspheres (denoted [3H]clinprost(LM)) was significantly inhibited by the endocytosis inhibitor, dansylcadaverine. The transport of LM into BCECs by endocytosis was also confirmed by fluorescence microscopy and flow-cytometric analysis using LM labelled with a fluorescent probe, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI). The absolute uptake of DiI(LM) by BCECs, measured by HPLC, was, however, almost 1/10 that of [3H]clinprost(LM), results which suggest the superiority of simple diffusion of clinprost over endocytosis of its LM form in the uptake of clinprost(LM) by BCECs. In the capillary-depletion study with rat-brain-perfused [3H]clinprost(LM) from the internal carotid artery, the parenchyma apparent distribution volume was about 45 times larger than that of the capillary, showing that [3H]clinprost(LM) was transported through the blood-brain barrier into the brain. The permeability coefficients of [3H]clinprost and [3H]clinprost(LM) determined by in-situ brain perfusion in normal rats were considerably higher than those of the active metabolite [3H]isocarbacyclin and its LM form. In addition, the Blood-brain-barrier permeabilities to [3H]clinprost, [3H]isocarbacyclin and their LM forms in ischaemic rats were almost identical to those in normal rats.
It was concluded that clinprost(LM) was transported through the blood-brain barrier by endocytosis of LM, simple diffusion of clinprost released from LM, and transport of isocarbacyclin generated by hydrolysis of clinprost. The blood-brain-barrier permeability of clinprost(LM) is not reduced in ischaemic conditions, because the simple diffusion of clinprost released from LM contributed mainly to clinprost(LM) transport.
Comparison of Two Binding Equations for Prediction of the Concentration of Unbound Valproic Acid in the Serum of Adult Epileptic Polytherapy Patients
Authors: Kodama Yasuo , Kuranari Masae , Kodama Hirofumi , Zaizen Takako , Yukawa Eiji , Fujii Isao , Takeyama Masaharu 
Published: April 2011

Abstract
Because binding of valproic acid to plasma proteins affects the efficacy of the drug in the treatment of epilepsy (only the unbound fraction of the drug is effective) we have compared two methods which use different binding parameters to predict the in-vivo concentration of unbound valproic acid in serum.
The study was performed on 46 serum samples from 29 polytherapy adult patients with epilepsy. Mean prediction error, mean absolute prediction error and root mean squared error were calculated for each method; these values served as a measure of prediction bias and precision. The mean absolute prediction errors and root mean squared errors for the two methods were similar in magnitude (Method 1, mean absolute prediction error= 10.0 μM, root mean squared error= 15.0 μM; Method 2, mean absolute prediction error= 10.3 μM, root mean squared error= 13.5 μM). Method 2 had a general tendency to over-predict unbound valproic acid; both methods had a tendency to over-prediction for total concentrations above 500 μM. Method 1 had a tendency to under-prediction at total concentrations below 250 μM. Within the total concentration range of valproic acid investigated, Method 1 was superior to Method 2 for prediction of unbound serum valproic acid.
Our approach using Method 1 may be useful for prediction of unbound serum valproic acid concentration in patients with total valproic acid concentrations ranging from 250 to 500 μM; Method 2 may be useful for patients with total valproic acid below 500 μM. Our results suggest that there is wide and unpredictable variability in valproic acid binding to serum proteins among study populations.
Effects of Enzyme Inhibitors and Insulin Concentration on Transepithelial Transport of Insulin in Rats
Authors: Bai Jane P F , Chang L L 
Published: April 2011

Abstract
The objective of this study was to determine whether transepithelial transport of insulin can be improved by enzyme inhibitors and whether insulin concentration affects its ileal absorption.
Ussing chambers and radioimmunoassay were used to study insulin transport across the rat ileum, and circular dichroic spectra were used to determine whether insulin aggregated at high concentrations. Inhibitors that inhibit insulin-degrading enzyme, including N-ethylmaleimide, 1,10-phenanthroline and N-chloromercuribenzoate, dramatically improved insulin transport across the ileum. At 100 nm, the ileal permeability of immunoreactive insulin was 10-6 cm s−1 in the presence of inhibitors, and was negligible when inhibitors were not used. Ammonium chloride, a lysosomotropic agent that increases intralysosomal pH, and aprotinin, a proteasome inhibitor, did not increase transport of insulin to a detectable extent. Insulin permeability decreased as its concentration increased from 100 nm to 83.3 μM, and at 83.3 μM insulin aggregated.
It is concluded that insulin transport is improved by enzyme inhibitors, but is impaired by insulin aggregation at high concentrations.
Active Secretion of Drugs from the Small Intestinal Epithelium in Rats by P-Glycoprotein Functioning as an Absorption Barrier
Authors: Terao Toshimitsu , Hisanaga Etsuko , Sai Yoshimichi , Tamai Ikumi , Tsuji Akira 
Published: April 2011

Abstract
Because the significance of P-glycoprotein in the in-vivo secretion of β-blockers in intestinal epithelial cells is unclear, the secretory mechanism for β-blockers and other drugs has been evaluated.
Uptake of the β-blockers acebutolol, celiprolol, nadolol and timolol, and the antiarrhythmic agent, quinidine by the multidrug-resistant leukaemic cell line variant K562/ADM was significantly lower than that by drug-sensitive K562 cells, suggesting that these β-blockers are transported by P-glycoprotein out of cells. The reduced uptake of acebutolol by the drug-resistant K562/ADM cells was reversed by treating the cells with anti-P-glycoprotein monoclonal antibody, MRK16, whereas no such alteration in uptake was observed for drug-sensitive K562 cells. Acebutolol uptake by K562/ADM cells was, moreover, markedly enhanced, in a concentration-dependent manner, in the presence of the specific P-glycoprotein inhibitors, MS-209 and cyclosporin. Caco-2 cells were used for evaluation of the role of P-glycoprotein in intestinal permeability to drugs in-vitro. Basolateral-to-apical transport of acebutolol was twice that in the reverse direction. A similar polarized flux was also observed in the transport of vinblastine, but not in that of acetamide or mannitol. When in-vivo intestinal absorption was evaluated by the rat jejunal loop method, with simultaneous intravenous administration of a P-glycoprotein inhibitor, cyclosporin, intestinal absorption of both acebutolol and vinblastine increased 2.6- and 2.2-fold, respectively, but no such enhancement was observed in the absorption of acetamide. The effect of cyclosporin on the intestinal absorption of several drugs was further examined, and the extent of the contribution of P-glycoprotein as an absorption barrier to those drugs was evaluated. ATP depletion by occlusion of the superior mesenteric artery resulted in a clear increase in epithelial permeability to vinblastine, but not to 3-O-methylglucose or acetamide, indicating that vinblastine is secreted by ATP-dependent P-glycoprotein into the lumen.
These findings demonstrate that P-glycoprotein plays a role as an absorption barrier by transporting several drugs from intestinal cells into the lumen.