bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Oral Mucoadhesive Microspheres in Man on the Basis of the Pharmacokinetics of Furosemide and Riboflavin, Compounds with Limited Gastrointestinal Absorption Sites
Authors: Akiyama Yohko , Nagahara Naoki , Nara Eiji , Kitano Megumi , Iwasa SUSUMU , Yamamoto Isamu , Azuma Junichi , Ogawa Yasuaki 
Published: April 2011

Abstract
When sustained-release adhesive and non-adhesive microspheres which release the same drugs at similar rates are administered orally, drug absorption after administration of adhesive microspheres should, if the gastrointestinal residence of adhesive microspheres is prolonged as a result of mucoadhesion, be higher than that after administration of non-adhesive microspheres. The gastrointestinal transit of oral adhesive microspheres in man has been evaluated pharmacokinetically using furosemide and riboflavin, compounds with limited absorption sites in the upper small intestine.
In a preliminary experiment with fasted rats it was confirmed that a higher percentage of the drug remained in the stomach and that plasma drug levels were higher when furosemide was administered in the form of adhesive rather than non-adhesive microspheres. Two kinds of sustained-release microsphere, adhesive and non-adhesive, containing furosemide and riboflavin in hard gelatin capsules were prepared and orally administered to 10 healthy fasted volunteers in a cross-over design. Areas under the plasma concentration-time curves (AUC) were 1.8 times larger for furosemide and urinary recovery was 2.4 times higher for riboflavin when adhesive microspheres rather than when non-adhesive microspheres were used. When adhesive microspheres containing riboflavin were administered to fed volunteers, urinary recovery was 2.1 times higher and mean residence time (MRT) was more prolonged than when the microspheres were administered to fasted volunteers.
Adhesive microspheres were found to adhere to the gastric or intestinal mucosa with high affinity in man and rats, resulting in prolonged gastrointestinal residence.
Pharmacokinetics and Haemodynamic Effect of Diltiazem in Rats: Effect of Route of Administration
Authors: Tsui Ban C H , Feng Joe D Z , Yeung Pollen K F 
Published: April 2011

Abstract
Diltiazem is a calcium antagonist widely used for the treatment of angina and hypertension. Previous studies in patients have shown that the haemodynamic effects of diltiazem are greater after parenteral rather than oral administration. The rat has been used as an animal model to determine the effect of the route of administration on the pharmacokinetic and haemodynamic effects of diltiazem.
The results showed that plasma concentrations of diltiazem were more than 10 times higher after the intra-arterial dose. The plasma concentrations of the major metabolites were also higher after intra-arterial administration, although only for deacetyl diltiazem (M1) did the difference reach statistical significance (P &lt; 0.05). The haemodynamic effects (on blood pressure and heart rate) of diltiazem were considerably greater after intra-arterial administration; this was attributed mainly to the much higher plasma concentrations of diltiazem. The hypotensive and chronotropic effects of diltiazem were similar; Emax and EC50 for diastolic blood pressure were 72 ± 19% and 4.4 ± 5.9 μg mL−1; for heart rate they were 77 ± 32% and 10.0 ± 11.7 μg mL−1, respectively.
The haemodynamic effects of diltiazem are much greater after intra-arterial administration, mainly because of the much higher plasma concentrations of the drug. The contribution by the metabolites would be minimal after this route of administration.
Analgesic and Thermic Effects, and Cerebrospinal Fluid and Plasma Pharmacokinetics, of Intracerebroventricularly Administered Morphine in Normal and Sensitized Rats
Authors: Bhargava Hemendra N , Villar Vincent M , Cortijo Julio , Morcillo Esteban J 
Published: April 2011

Abstract
The relationship between asthma and opioids has barely been investigated. This study examines whether active sensitization of rats changes the analgesic and thermic effects of intracerebroventricular morphine or the pharmacokinetics of the drug.
Morphine (5, 10 and 20 μg) was given intracerebroventricularly to sensitized (active immunization to ovalbumin and Al(OH)3 then airway challenge with ovalbumin after 12 days) and normal (i.e. non-sensitized) male Sprague-Dawley rats. The tail-flick latencies and changes in colon temperature were determined before morphine injection and at 30 min intervals for a period of 300 min afterwards. Results were expressed as the area under the time-response curve. The analgesic and hyperthermic response to morphine for sensitized rats was less than that obtained for normal rats. Cerebrospinal fluid and blood samples were collected periodically for a period of 240 min and morphine levels were determined by a highly sensitive radioimmunoassay. The pharmacokinetic parameters half-life, terminal elimination rate constant and the mean residence time were determined in both cerebrospinal fluid and plasma by non-compartmental analysis. The area under the cerebrospinal fluid concentration-time curve from time zero to infinity was higher for sensitized rats than for normal rats for all three doses of morphine but these differences did not correspond with similar changes in pharmacological responses.
In conclusion, the attenuated analgesic and thermic responses to intracerebroventricular morphine in the sensitized rats might be a result of pharmacodynamic alterations rather than to pharmacokinetic changes.
Differential Effects of Nicorandil on the Vasodepressor Responses to Vasoactive Polypeptides Administered Intravenously to Rats
Authors: Sakai Kazushige , Akima Michitaka , Saito Keiji 
Published: April 2011

Abstract
The effects of nicorandil on vasodepressor responses to vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and substance P have been examined in anaesthetized rats.
Intravenous bolus injections of VIP (0.3 μg kg−1), CGRP (0.1 μg kg−1) and substance P (0.1 μg kg−1) induced reductions of blood pressure accompanied by slight increases (less than 5%) in heart rate. Nicorandil infused intravenously at 10 or 30 μg kg−1 min−1 significantly augmented the vasodepressor responses to VIP and CGRP but did not modify the responses to substance P and acetylcholine (0.1 μg kg−1). Intravenous treatment with glibenclamide (20 μg kg−1) significantly attenuated not only the vasodepression caused by VIP and CGRP, but also the enhancement of the effects of the agents by nicorandil.
These results indicate that nicorandil can enhance the action of VIP and CGRP, in rats, at least partly through ATP-sensitive K+-channel activation.
Effects of Sho-saiko-to on the Pharmacokinetics and Pharmacodynamics of Tolbutamide in Rats
Authors: Nishimura Nobuhiro , Naora Kohji , Hirano Hidenari , Iwamoto Kikuo 
Published: April 2011

Abstract
Although Sho-saiko-to (Xiao Chai Hu Tang), a major Chinese traditional medicine, is frequently prescribed with other synthetic or biotechnological drugs for the treatment of various chronic diseases, there is a dearth of information about interactions between sho-saiko-to and co-administered drugs. This paper reports the effects of Sho-saiko-to on the pharmacokinetics and glucose responses of a sulphonylurea hypoglycaemic agent, tolbutamide, after their oral administration in rats.
After oral administration of tolbutamide (50 mg kg−1) with or without Sho-saiko-to extract powder (300 mg kg−1) to male Sprague-Dawley rats cannulated in the jugular vein, plasma tolbutamide and glucose levels were periodically measured. Co-administration of Sho-saiko-to tended to elevate the plasma tolbutamide concentration in the absorption phase. A two-compartment lag-time model was found to describe the plasma tolbutamide concentration-time data. The maximum concentration of tolbutamide was significantly increased and time to reach the maximum concentration was reduced to about 70% by co-administration with Sho-saiko-to. There was no significant change in area under the curve or in the elimination half-life of tolbutamide. The extent of the lowering effect of tolbutamide on plasma glucose levels was increased up to 0.75 h and decreased after 5 h after co-administration of Sho-saiko-to.
In conclusion, these studies suggest that sho-saiko-to slightly hastens the gastrointestinal absorption of tolbutamide. Furthermore, it is considered that elevation of the gastrointestinal absorption rate by Sho-saiko-to might potentiate the hypoglycaemic effect of this sulphonylurea in the early period after oral administration.
Extensive Binding of the Bioflavonoid Quercetin to Human Plasma Proteins
Authors: Boulton David W , Walle U Kristina , Walle Thomas 
Published: April 2011

Abstract
Although the bioflavonoids, a large group of polyphenolic natural products, exert chemopreventive effects in cardiovascular disease and cancer, there is little information about the disposition of these dietary components in man. The objective of this study was to investigate the plasma-protein binding of the most abundant bioflavonoid, quercetin, using 14C-labelled quercetin.
An ultracentrifugation assay (170 000 g for 16 h at 20°C) was shown to sediment plasma proteins. Binding of quercetin to normal plasma was extensive (99.1 ± 0.5%, mean ± s.d., n = 5). The unbound fraction varied as much as 6-fold, 0.3–1.8%, between subjects. This high binding was independent of quercetin concentration over the range 1.5–15 μM (0.5–5 μg mL−1). Human serum albumin was the primary protein responsible for the binding of quercetin in plasma (99.4 ± 0.1%). Binding by α1-acid glycoprotein (39.2 ± 0.5%) and very-low-density lipoproteins (&lt; 0.5% of total quercetin) did not make substantial contributions to overall plasma binding. The equilibrium association constant for the binding of quercetin to serum albumin was 267 ± 33 times 103 M−1 (n=15). Thermodynamic data for the binding of quercetin to serum albumin indicated spontaneous, endothermic association. Displacement studies suggested that in man the ‘IIA’ subdomain binding site of human serum albumin was the primary binding site for quercetin. Association of quercetin with erythrocytes was significantly (P &lt; 0.001) reduced by plasma protein binding.
These data indicate poor cellular availability of quercetin because of its extensive binding to plasma proteins.
N- Acetyl-L-γ-glutamyl Derivatives of p-Nitroaniline,
Sulphamethoxazole and Sulphamethizole for Kidney-specific
Drug Delivery in Rats
Authors: Murakami Teruo , Kohno Kumiko , Yumoto Ryoko , Higashi Yutaka , Yata Noboru 
Published: April 2011

Abstract
Kidney-specific delivery of p-nitroaniline, sulphamethoxazole and sulphamethizole after either intravenous administration of the L-γ-glutamyl or N-acetyl-L-γ-glutamyl derivatives or the parent drugs has been examined in a rat model.
All L-γ-glutamyl derivatives were converted to the corresponding parent drugs within 60 min whereas the N-acetyl-L-γ-glutamyl derivatives were fairly stable in the systemic circulation after parenteral administration. Concentrations of p-nitroaniline and sulphamethoxazole 20 min after administration of the parent drugs were somewhat higher in the kidney than in the liver and lung. The concentration of sulphamethizole in the kidney was dramatically higher than those in the hepatic and pulmonary tissue. Kidney-specific delivery of the drugs of interest was evaluated by determining the tissue concentrations of the released parent drug and the total drug levels (i.e. drug levels after hydrolysis of all conjugate to the parent drug). For L-γ-glutamyl-p-nitroaniline released renal levels of p-nitroaniline and total p-nitroaniline concentrations were both higher than those obtained after p-nitroaniline dosing. Use of L-γ-glutamylsulphamethoxazole resulted in higher total sulphamethoxazole concentrations in the kidney, but did not lead to an increase in released (unconjugated) sulphamethoxazole levels. In contrast, no kidney-selective distribution was observed for L-γ-glutamylsulphamethizole. Markedly increased kidney distribution was observed for both N-acetyl-L-γ-glutamyl-p-nitroaniline and N-acetyl-L-γ-glutamylsulpha-methoxazole and the liver and lung concentrations were correspondingly reduced in comparison with parent drug dosing. Use of the N-acetyl-L-γ-glutamyl-p-nitroaniline conjugate increased the concentration of p-nitroaniline in the kidney to the same extent as did L-γ-glutamyl-p-nitroaniline.
In conclusion, N-acetyl-L-γ-glutamyl derivatization of certain compounds seems to be useful for kidney-specific ***drug delivery and preliminary data suggests that lipophilic drugs are better substrates than hydrophilic compounds. Results related to the selectivity of tissue distribution of the derivatives and species differences are discussed.
The Effect of a Drug-delivery System Consisting of Soybean Phosphatidyl Choline and Medium-chain Monoacylglycerol on the Intestinal Permeability of Hexarelin in the Rat
Authors: Fagerholm Urban , Sjöström Brita , Sroka-Markovic Janina , Wijk Annika , Svensson Marianne , Lennernäs Hans 
Published: April 2011

Abstract
The aim of this study was to investigate if the effective in-situ permeability (Peff) of a new growth hormone-releasing peptide, hexarelin, along rat intestine was enhanced by a lipid matrix drug-delivery system comprising a mixture of soybean phosphatidyl choline and medium-chain monoacylglycerol (PC-MG). The study was performed with and without a protease inhibitor, Pefabloc SC. To enable better understanding of the mechanism of action of this delivery system we also studied the uptake of a small hydrophilic molecule, atenolol.
PC-MG at a concentration of 15 mmol L−1 increased the jejunal Peff of hexarelin approximately 20-fold, both in the presence and absence of Pefabloc SC, whereas Peff was not increased in the ileum and colon. PC-MG had no effect on the jejunal, ileal and colonic Peff of atenolol. Complete recovery of the non-absorbable molecule PEG 4000 showed that functional intestinal viability was maintained in all experiments.
Although the results obtained in this study are promising, pharmacokinetic and toxicological studies are required to investigate if this delivery system is a suitable and safe candidate for improving the oral bioavailability of hexarelin.
Novel 5,8-Diazabenzo[c]phenanthrenes: Synthesis and Mutagenicity
Authors: Upton Mathew , Jaeda Moussa I , Upton Christopher 
Published: April 2011

Abstract
The polycyclic aromatic hydrocarbons have been recognized as carcinogens and mutagens since the early part of this century. More recently their aza and polyaza derivatives have been shown to have the same biological activity. A major source of these compounds is the combustion of fresh or metamorphosed plant materials; this contributes to the environmental burden of, and exposure to, these carcinogens. We report the synthesis and characterization of a series of novel 5,8-diazabenzo[c]phenanthrenes which are isosteric with the known epidermal carcinogen benzo[c]phenanthrene but have not yet been reported as components of soot or diesel particulate matter.
The synthesis of the compounds exploits a versatile, double Friedlander reaction between the appropriately substituted 2,2′-diaminobenzophenone and β-diketones, with yields of purified product ranging from 30–90%. The nucleophilic substitution of these diazabenzophenanthrenes with ethanolamine is also described. This strategy will enable further elaboration of these heterocyclic nuclei at a later date.
Mutagenicity testing of these agents was performed using spot tests and in Ames plate-incorporation assays using Escherichia coli WP2 and WP2uvrA as test organisms. The plate-incorporation assays were performed in the presence or absence of metabolic enzymes contained in the S9 liver fraction from Aroclor 1254-induced rats, to investigate whether bioactivation of the diazabenzophenanthrenes contributed to their toxicity. No differences between these two protocols were observed, with neither test showing reversion to prototrophic behaviour. Furthermore, the compounds were not toxic to the test organism.
These initial results suggest that these compounds are not mutagenic in the Ames tests employed.
Investigation into the Presence of Insulin-degrading Enzyme in Cultured Type I1 Alveolar Cells and the Effects of Enzyme Inhibitors on Pulmonary Bioavailability of Insulin in Rats
Authors: Hsu Matt Cheng-Pang , Bai Jane P F 
Published: April 2011

Abstract
The purpose of this study was to investigate the role of insulin-degrading enzyme (IDE, EC 3.4.22.11) in insulin degradation in alveolar epithelium. The primary culture of isolated rat type-II pneumocytes was used for the in-vitro characterization of IDE. Insulin was then administered intratracheally with various inhibitors to assess the improvement in its pulmonary bioavailability.
In cultured type-II pneumocytes, the cytosolic insulin-degrading activity contributed 81% of total insulin degradation, reached a maximum at pH 7-5 and had an apparent Michaelis-Menten constant (Km) of 135 nM. N-Ethylmaleimide, p-chloromercuribenzoic acid and 1,10-phenanthroline inhibited insulin-degrading activity almost completely in both crude homogenate and cytosol. An immunoprecipitation study showed that IDE contributed 74% of cytosolic insulin-degrading activity. Western blot analysis showing a single band of 110 kDa on reduced SDS (sodium dodecylsulphate) gels confirmed the presence of IDE in cultured type-II cells. When given intratracheally with insulin, inhibitors including N-ethylmaleimide, p-chloromercuribenzoic acid, and 1,10-phenanthroline significantly enhanced the absolute bioavailability of insulin and the compound’s hypoglycaemic effects.
These results suggest that IDE is present in alveolar epithelium and might be involved in limiting insulin absorption in the lung.
Effects of 17β-Oestradiol on Rat Isolated Coronary and Mesenteric Artery Tone: Involvement of Nitric Oxide
Authors: Otter Donna , Austin Clare 
Published: April 2011

Abstract
Pre- and post-menopausal women receiving oestrogen replacement therapy have a significantly reduced risk of cardiovascular disorders. It has been suggested that this protection might be partly a result of a direct relaxant effect of oestrogens on coronary arteries. This study examines and directly compares the effects of 17β-oestradiol on rat isolated coronary and mesenteric vessels. The influence of nitric oxide on these responses was also investigated.
17β-Oestradiol caused similar concentration-dependent relaxation of isolated coronary and mesenteric resistance arteries pre-contracted with either KCl (60 mM) or 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin (U46619; 1 μM). The relaxation responses to 17β-oestradiol were significantly reduced, but not totally inhibited, in the presence of Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase; they were not altered by indomethacin, an inhibitor of prostaglandin synthesis. The responses to 17β-oestradiol in the presence of L-NAME were not dependent on the vessel studied or the precontracting agent used.
These results suggest that nitric oxide might contribute to the vasodilatory effects of 17β-oestradiol in rat isolated coronary and mesenteric resistance arteries.
5-Hvdroxvtrvotamine-induced Secretion bv Rat Jeiunum In-vitro Involves Several 5-Hydroxytryptamine Receptor Subtypes
Authors: Hardcastle J , Hardcastle P T 
Published: April 2011

Abstract
The receptors contributing to 5-hydroxytryptamine (5-HT)-induced anion secretion by rat jejunum have been investigated by testing the effects of selective agonists and antagonists in-vitro using both intact and stripped intestinal sheets.
In both intact and stripped jejunum 5-HT and 5-methoxytryptamine, an agonist that lacks affinity for 5-HT3 receptors, induced concentration-dependent increases in the short-circuit current (SCC), although 5-methoxytryptamine induced a smaller maximum response. In intact sheets 1-phenylbiguanide, a selective 5-HT3 agonist, induced a response that was similar in magnitude to that of 5-methoxytryptamine, but in stripped preparations it had little effect. Tetrodotoxin inhibited the response of intact jejunum to 5-HT (by 86%) and 5-methoxytryptamine (by 85%) and abolished the response to 1-phenylbiguanide. In stripped sheets inhibition of the 5-HT response by tetrodotoxin was reduced to 27%. Desensitization to 1-phenylbiguanide reduced the response to 5-HT in intact but not stripped sheets whereas, in contrast, desensitization to 5-methoxytryptamine inhibited the 5-HT response in stripped sheets but was without effect in intact sheets. Mianserin, a 5-HT1, 5-HT2 and 5-HT3 antagonist, and renzapride, a 5-HT1 and 5-HT3 antagonist, both reduced the maximum response to 5-HT, but 5-HTP-DP, a 5-HT1 antagonist, was without effect. The 5-HT3 antagonist granisetron reduced the response to 5-HT in intact, but not in stripped sheets. Tropisetron, a 5-HT3 and 5-HT4 antagonist, inhibited the response to 5-methoxytryptamine in both preparations, but did not alter the response to 5-HT.
It is concluded that 5-HT-induced jejunal secretion involves more than one 5-HT receptor subtype, with both neural and non-neural mechanisms contributing to the response.
Flavonoids Reduce Morphine Withdrawal In-vitro
Authors: Capasso A , Piacente S , Pizza C , Sorrentino L 
Published: April 2011

Abstract
The effects of quercetin, flavone, catechin and chrysin on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum have been investigated in-vitro.
After 4 min in-vitro exposure to morphine a strong contracture of guinea-pig isolated ileum was observed after the addition of naloxone. All the flavonoids, injected 10 min before morphine at concentrations between 10−7 and 10−5 M, were capable of blocking naloxone-induced contracture after exposure to morphine in a concentration-dependent fashion. IC50 values calculated for quercetin, flavone, catechin and chrysin were 2.7 times 10−6, 7.3 times 10−7, 8.5 times 10−7 and 5.3 times 10−6 M, respectively.
These results suggest that flavonoids might play an important role in the control of morphine withdrawal.
Study of the Interaction of Dithranol with Heptakis( 2,3,6-tri-O-methyl)-β-cyclodextrin in Solution and in the Solid State
Authors: Cafaggi Sergio , Vallarino Marisa , Caviglioli Gabriele , Parodi Brunella , Bignardi Gaetano 
Published: April 2011

Abstract
The interaction between dithranol and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TMBCyD) has been investigated in aqueous solution containing isoascorbic acid (0·2% w/v) as antioxidant and in the solid state. The interaction in the solid state was studied by differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray powder diffractometry (XPD) and a dissolution-rate method.
The extent of complexation between the two substances was poor, as indicated by the low value of the slope of the linear part of the solubility curve. A phase diagram was constructed by measuring the thermal behaviour of various re-solidified physical mixtures of dithranol and of TMBCyD previously subjected to heating until melting of the TMBCyD. The loss of dithranol, owing to sublimation and degradation caused by the thermal treatment used, was less than 10%. In keeping with XPD and IR data, the phase diagram indicated that a complex was formed containing 13·7% dithranol (molar ratio 1:1) which had a congruent melting point at 164°C. The drug dissolution rate from the 1:1 complex was measurable, unlike that of the corresponding physical mixture, and was significantly increased when the complex was dispersed in the glassy matrix of TMBCyD, as it was in re-solidified mixtures containing 2–7% dithranol.
The results show that the solubility of dithranol is increased significantly as a consequence of its interaction with TMBCyD, despite the low extent of complexation between the two substances.