bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies on the Toxicity of Analogues of Dapsone In-vitro Using Rat, Human and Heterologously Expressed Metabolizing Systems
Authors: Coleman Michael D , Smith Stephen N , Kelly Diane E , Kelly Steven L , Seydel Joachim K
Published: April 2011

Three metabolizing systems (rat, heterologously expressed CYP3A4 and human liver) were used to evaluate 12 analogues of dapsone (4,4′diaminodiphenylsulphone) in-vitro. Methaemoglobin formation in a two-compartment and cytotoxicity in a single-compartment model were studied using human erythrocytes and neutrophils, respectively, as target cells.

In the two-compartment system using rat microsomes as a generating system and methaemoglobin as an end-point, the least potent methaemoglobin formers tested were the 2-methyl-4-propylamino (AXDD14), 2-hydroxy-4-4′amino (ABDD5) derivatives and a sulphone/trimethoprim derivative (K-130). Dapsone itself, a 2-methoxy-4-ethylamino (W10) and a 2-hydroxyl-4-ethylamino compound (ABDD39) were the most toxic. In the single-compartment cytotoxicity test using rat microsomes, AXDD14 was again among the least toxic, as was a 2-methyl 4-cyclopentyl derivative (AXDD17) and surprisingly ABDD39. The most cytotoxic compounds again included dapsone itself as well as two 2-trifluoromethyl derivatives. The only significant methaemoglobin formation and cytotoxicity shown with the heterologously expressed human CYP 3A4 was with AXDD14, which was extensively activated. Interestingly, metabolism of dapsone was low using the expressed CYP 3A4.

In the two-compartment system using human liver microsomes, AXDD14, K-130 and ABDD5 were oxidized to a significantly lesser extent compared with dapsone and these preliminary findings indicate that future development of these compounds may be worthwhile.
Inhibitory Effects of (±)-Tetrahydropalmatine on Thyrotropin-stimulating Hormone Concentration in Hyperthyroid Rats
Authors: Hsieh Ming-Tsuen , Wu Long-Yuan
Published: April 2011

The effects of (±)-tetrahydropalmatine ((±)-THP) on the hypothalamus-pituitary-thyroid system in rats were investigated.

Thyroid function experiments indicated that (±)-THP produces significant decreases in thyroid function in hyperthyroid rats after 14 days of treatment. These effects were the same as those of propylthiouracil. However, propylthiouracil also decreased thyroid function in normal rats. Measurements of thyrotropin-stimulating hormone (TSH) demonstrated that (±)-THP decreased TSH in hyperthyroid rats after 14 days of treatment; however, propylthiouracil increased TSH in hyperthyroid rats. (±)-THP had no influence on TSH, or thyroid and pituitary weight in normal and hyperthyroid rats.

We conclude that (±)-THP has an antithyroid function and the mechanism of action may be related to the inhibition of TSH in the pituitary.
The Antistaphylococcal Effect of Nisin in a Suitable Vehicle: A Potential Therapy for Atopic Dermatitis in Man
Authors: Valenta Claudia , Bernkop-SchnüRch Andreas , Rigler Hans Peter
Published: April 2011

Staphylococcus aureus plays a central role in the pathogenesis of atopic dermatitis and is the predominant microorganism both in the lesions and in adjacent clinically normal skin. Chronic infection might aggravate the underlying lesion and serve as a source for further S. aureus infection. Nisin is a non-toxic and non-irritant peptide with no antibiotic-like side effects.

In this study the antistaphylococcal activity of nisin in six topical formulations was investigated in diffusion tests and is shown to depend both on the water content and on the technological system. Because topical products often adhere to the stratum corneum for only a short time, the kinetics of antimicrobial activity were examined using a membrane filter technique. Thirty minutes after nisin addition almost no living microorganisms were detectable in different aqueous samples.

The results demonstrate the potential of nisin preparations as an alternative to common antibiotics in the treatment of S. aureus infections in atopic dermatitis.
Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules
Authors: Samanen James , Wilson Glynn , Smith Philip L , Lee Chao-Pin , Bondinell William , Ku Thomas , Rhodes Gerald , Nichols Andrew
Published: April 2011

This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/ IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided.

The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.
Preparation of Dipeptoid Mimetics for the Tetrapeptide Cholecystokinin, CCK(30–33)
Authors: Walford S P , Campbell M M , Horwell D C
Published: April 2011

The diastereoselective synthesis of 2,3-methanophenylalanine methyl esters (5) has been achieved in 58% yield. The preparation of the dehydropeptides (1, R = Me; 2, R = H) and the cyclopropylpeptides (3, R = Me; 4, R = H) possessing good binding affinities for the CCK-A and CCK-B receptors is described. Conformational studies of the dipeptide esters 1 and 3 indicated the presence of a β-turn within the peptide backbone, although there was no preference in type. The Phe and Trp moieties, however, did prefer to be situated on the same side of the peptide turn which is favourable for receptor binding.
Studies with Inhibitors of the Glycolytic Enzyme Phosphoglycerate Kinase for Potential Treatment of Cardiovascular and Respiratory Disorders
Authors: McHarg J , Littlechild J A
Published: April 2011

Inhibition of the glycolytic enzyme phosphoglycerate kinase (PGK) in erythrocyte cells could provide a method of treatment for cardiovascular and respiratory disorders. The product of the reaction catalysed by PGK, 1,3-diphosphoglycerate, is converted by another enzyme in erythrocytes to 2,3-diphosphoglycerate, which is an allosteric effector of haemoglobin. For this reason, a series of fluoro-phosphonate inhibitors have been tested for their potency in detailed inhibition kinetic experiments with yeast PGK.

The results were analysed by Lineweaver-Burk and Dixon plots and Ki values obtained. Two fluorophosphonates were found to be inhibitory and both have an electron rich mid-chain functionality, which is thought to provide electrons for hydrogen bonding to residues in the triose binding site of the enzyme.

It is postulated that either the fluorine or mid-chain moieties of the analogues are binding to Asp23 and Asn25 residues in the so called ‘basic patch’ area of the triose site. These residues are shown to bind to the D-hydroxyl moiety on the C2 of the true substrate, 3-phosphoglycerate, in the high-resolution crystal structure of pig muscle PGK co-crystallized with 3-phosphoglycerate.
Molecular Modelling of β Turns in a Cyclic Melanotropin
Authors: Chan Ngai Chung , Branch Sarah K , Moss Stephen H , Pouton Colin W
Published: April 2011

α-Melanocyte stimulating hormone (α-MSH) is a tridecapeptide which interacts with a family of G protein-coupled receptors, the melanocortin receptors, to cause its biological effects.

We have modelled the low energy conformations of the α-MSH derivatives as part of a project to probe the receptor binding conformation of melanocortins, and also to design ligands for targeting cytotoxic drugs to MC1 receptors expressed by melanoma cells. H***ere we report a molecular dynamics study of β turns in a cyclic lactam analogue [Nle4, ***Asp5, D-Phe7, Lye***10]α-MSH.

The data show that it is possible for a β turn to exist in the ring portion of this molecule which contains the melanocortin conserved sequence -His-Phe-Arg-Trp-, even though the lowest energy conformers lack a β turn.
The MS-MS Determination of the Fragmentation Pathways of Some Substituted 1,2,3-Benzotriazin-4-ones with Possible Applications in Metabolic Studies
Authors: Woodland E D , Lawson G , Ostah N
Published: April 2011

1,2,3-Benzotriazin-4-one derivatives are extensively used as herbicides, insecticides and nematicides. Incorporation of these compounds into the human food chain is a cause for concern, since their toxicity to man is well documented.

This work describes the development of a data-base of classical 1,2,3-benzotriazin-4-one fragmentation patterns and consequent sequential neutral mass losses which allows the prediction of the presence of a triazinone derived compound.

Positive and negative ion tandem mass spectrometry techniques were employed since they allow rapid and sensitive structural characterization of drugs and their metabolites in biological fluids through the unambiguous monitoring of daughter ions from pre-selected primary ions.
Effects of Different Absorption Enhancers on the Permeation of Ebiratide, an ACTH Analogue, across Intestinal Membranes
Authors: Yamamoto Akira , Okagawa Taishi , Kotani Atsushi , Uchiyama Tomomi , Shimura Takesada , Tabata Shigeru , Kondo Shuji , Muranishi Shozo
Published: April 2011

The permeation of ebiratide (H-Met(O2)-Glu-His-Phe-d-Lys-Phe-NH(CH2)8NH2), a novel ACTH analogue, across the intestinal mucosae has been examined by use of isolated intestinal membranes from rats in a modified Ussing chamber.

Regional differences were observed in the permeation of ebiratide across intestinal membranes; the order of membrane permeability was jejunum > ileum > duodenum > colon. Overall, the permeation of ebiratide was relatively poor. The effects of various absorption enhancers were examined to increase the intestinal permeability to ebiratide. Sodium glycocholate and sodium caprate had no significant enhancing effect on the permeability of the jejunal membrane, but significantly enhanced the permeation of ebiratide through the colonic membrane. On the other hand, N-dodecyl-β-d-maltopyramoside (LM) significantly enhanced the permeation of ebiratide through both jejunal and colonic membranes. In general, the absorption-enhancing effects of these agents were more predominant in the colon than in the jejunum. Membrane damage by the absorption enhancers was evaluated by measuring the amount of protein released from the intestinal membrane. It was found that all the absorption enhancers slightly increased the amount of protein released, but that the amounts of protein released in the presence of these enhancers were much less than in the presence of ethylenediaminetetraacetic acid (EDTA), used as a positive control.

These findings suggest that the absorption enhancers, especially LM might be useful adjuvants for improving the intestinal absorption of peptide and protein drugs, including ebiratide.
Twenty-four-hour Variations in the Effect of Nitrodilators in Rat Aorta: Lack of Influence of the Endothelium
Authors: Hodoglugil Ugur , Uluoglu Canan , Güney H Zafer , Görgün C Zafer , Ercan Z Sevim , Abacioglu Nurettin , Zengil Hakan
Published: April 2011

Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitrate on isolated smooth muscle have been studied on rings of rat thoracic aorta, both endothelium-intact and endothelium-denuded.

For most of the concentrations of sodium nitroprusside used the induced relaxations were significantly dependent on the time the tissues were obtained. However, significant temporal differences were obtained for glyceryl trinitrate-induced relaxations at lower concentrations only for both endothelium-intact and endothelium-denuded preparations. EC50 values of sodium nitroprusside and glyceryl trinitrate (i.e. the concentrations inducing half the maximum response) were also significantly different and they had quite similar rhythmic features both in endothelium-intact and in endothelium-denuded preparations.

These results clearly show that the in-vitro sensitivity of rat thoracic aorta to nitrodilator agents varies over a 24-h period and thus depends on when the animals were killed; the presence of endothelium does not change the rhythm of nitrodilator activity. These variations might be a result of circadian rhythm in the guanylate cyclase-cGMP system which mediates responses to nitrodilator agents.
Effect of Ganglionic Blocking Compounds on In-vivo Fluid Secretion in the Rat Small Intestine
Authors: Delbro Dick S , Lange Stefan
Published: April 2011

It is well-known that enteric, secreto-motor nerves mediate cholera toxin-induced fluid secretion in the rat small intestine. This notion is, in part, derived from experiments on anaesthetized animals in which the response to cholera toxin was antagonized by the ganglionic nicotinic receptor antagonist, hexamethonium. In the current study, such anti-secretory action of ganglionic blocking compounds was analysed in an experiment designed to minimize any possible negative effect of general anaesthesia on intestinal secretion.

Rats were anaesthetized with ether for 5–10 min, during which time a jejunal loop (10–12 cm) was constructed. The loop was challenged with one of the secretagogues, cholera toxin, prostaglandin E1 (PGE1) or okadaic acid. Saline (control) or either of the ganglionic blockers, hexamethonium and chlorisondamine, was administered intravenously. The rats were killed 5 h (cholera toxin) or 1–5 h (PGE1 and okadaic acid) after challenge, and the amount of fluid accumulated in the loops was determined. Cholera toxin-induced secretion was unchanged by hexamethonium but reduced by approximately 80% by chlorisondamine. The difference in effect between the two blockers might relate to the duration of ganglionic blockade. Chlorisondamine blocked secretion induced by either PGE1 or okadaic acid by approximately 60%.

It is suggested that the anti-secretory effect of ganglionic blocking compounds might be a result of blockade of secreto-motor nerves but other mechanisms, for example interference with haemodynamic factors, cannot be ruled out.
The Development of Nao Li Shen and its Clinical Application
Authors: Lu Shou-Long , Liu Xin , Wang Jian-Long , Ying Qi , Hu SHUI-GEN , Hu Ping-Ping , Zhu Guo-Ping , Zhen Hua-Wu , Bai Ying-Tang , Wang Quan
Published: April 2011

The traditional Chinese medicine Nao Li Shen (containing ginseng, gastrodia tuber, chuanxiong rhizome and red sage root) is used in craniocerebral injury, cervical spondylosis and cerebrovascular diseases.

The preparation, as an orally administered liquid, was tested in Mongolian gerbils and shown to increase tolerance to ischaemia and anoxia. Clinical use of the preparation resulted in improvement in 96% of 202 patients, as judged by right cerebral blood flow, TCD and CT examination.

We conclude that Nao Li Shen has a positive curative effect upon craniocerebral injury and sequelae of cerebrovascular diseases.
Effects of Administration of Phentonium Bromide on Opioid Withdrawal Syndrome in Rats
Authors: Pinelli A , Trivulzio S , Tomasoni L
Published: April 2011

This study has tested whether phentonium bromide, a quaternary ammonium anti-muscarinic agent, could reverse the signs of precipitated opioid withdrawal.

Rats were treated with either saline or morphine for 4 days, after which half the rats received naloxone and half saline. Each animal also received one of four doses of phentonium bromide (0, 1, 3 and 9 mg kg−1, i.p.). Administration of phentonium bromide in rats receiving naloxone after chronic morphine treatment reduced the intensity of withdrawal signs such as increased defecation or micturition, salivation and wet-dog shakes, and elevated the nociceptive threshold values.

The effects of administration of phentonium bromide might result from its anti-muscarinic activity interfering peripherally with the mechanisms involved in the regulation of the withdrawal symptoms. The use of this drug is thus suggested as a possible means of controlling some of the signs observed during the acute phase of opioid withdrawal in heroin addicts.
Post-ischaemic Alteration of Excitatory Amino Acid Transport Sites in the Gerbil Hippocampus
Authors: Araki Tsutomu , Kato Hiroyuki , Kogure Kyuya , Itoyama Yasuto
Published: April 2011

Sodium-dependent [3H]d-aspartate binding as a marker of excitatory amino acid transport sites in the gerbil hippocampus was evaluated by quantitative receptor autoradiography 1 h to 7 days after transient cerebral ischaemia for 10 min.

Sodium-dependent [3H]d-aspartate binding in the hippocampal CA1 and CA3 sectors significantly increased in the early post-ischaemic stage. After 7 days, a conspicuous elevation of sodium-dependent [3H]d-aspartate-binding was observed in the hippocampal CA1 sector and dentate gyrus. However, no significant change in the binding was found in the hippocampal CA3 sector. A histological study revealed that transient ischaemia caused severe neuronal damage in the hippocampal CA1 sector and mild damage in the hippocampal CA3 sector. However, no ischaemic neuronal damage was observed in the dentate gyrus. An immunohistochemical study also showed that numerous reactive astrocytes were evident in the hippocampus, particularly in the hippocampal CA1 sector, 7 days after ischaemia.

These results demonstrate that transient cerebral ischaemia can cause marked elevation in excitatory amino-acid transport sites in the hippocampus. Furthermore, our results suggest that the post-ischaemic increase in excitatory amino acid transport sites might reflect expression of reactive astrocytes. These findings are of interest in relation to the mechanisms of ischaemic hippocampal damage.
The Expanded Hansen Approach to Solubility Parameters. Paracetamol and Citric Acid in Individual Solvents
Authors: Barra Jerome , Lescure François , Doelker Eric , Bustamante Pilar
Published: April 2011

In this study two solubility-parameter models have been compared using as dependent variables the logarithm of the mole fraction solubility, lnX2e, and ln(α)/U (originally used in the extended Hansen method), where α is the activity coefficient and U is a function of the molar volume of the solute and the volume fraction of the solvent.

The results show for the first time the proton-donor and -acceptor hydrogen-bonding capacities of paracetamol, as measured by the acidic and basic partial-solubility parameters. The influence of solvents on the differential scanning calorimetry (DSC) pattern of the solid phases was also studied in relation to the solubility models tested. Citric acid was chosen as a test substance because of its high acidity and its proton donor capacity to form hydrogen bonds with basic solvents. The partial acidic and basic solubility parameters obtained from multiple regression were consistent with this property, validating the model chosen.

The results show that the more direct lnX2e variable was more suitable for fitting both models, and the four-parameter model seemed better for describing the interactions between solvent and solute.
Effect of Oral Adsorbent AST-120 on Cyclosporin Absorption in Rats
Authors: Takemoto M , Tsuchida M , Konishi M , Suga A , Jojima K , Naito K
Published: April 2011

The oral adsorbent AST-120 is used to inhibit the progression of renal failure by adsorbing uraemic toxins in the gastrointestinal tract. When AST-120 is administered to patients receiving immunosuppressive medicines, it is important to study the effect of AST-120 on the amount of these and other drugs absorbed. We have, therefore, studied the in-vitro adsorption of cyclosporin by AST-120 and investigated the effect of oral administration of AST-120 on the absorption of cyclosporin in rats.

The in-vitro adsorption ratios of AST-120 for cyclosporin were more than 80%. When pure cyclosporin powder was administered with AST-120, blood cyclosporin concentrations were significantly higher than when cyclosporin was administered alone. When cyclosporin dissolved in medium-chain triglyceride was administered to rats by intramuscular injection there was no significant difference in the blood cyclosporin concentration of rats given combined AST-120 and cyclosporin and those given cyclosporin alone. There was no significant difference between the serum concentration of total bile acids, in rats receiving combined oral AST-120 and cyclosporin dissolved in olive oil, and those receiving orally solely a solution of cyclosporin dissolved in olive oil.

These results suggest that oral administration of AST-120 accelerates the absorption of orally administered cyclosporin from the gastrointestinal tract and does not affect the metabolism of cyclosporin. When a solution of cyclosporin in olive oil is administered orally, however, oral administration of AST-120 has no influence on cyclosporin absorption and does not affect the enterohepatic circulation of bile acids.
A Residence-Time Distribution Analysis of the Hydrodynamics within the Intestine in Man during a Regional Single-pass Perfusion with Loc-I-Gut: In-vivo Permeability Estimation
Authors: Lennernäs Hans , Lee I-Der , Fagerholm Urban , Amidon Gordon L
Published: April 2011

The goal of this study was to determine the most appropriate hydrodynamic model for the Loc-I-Gut in-vivo perfusion system. The general mixing-tank-in-series model, which can approximate single mixing tank and laminar and plug-flow hydrodynamics, was fitted to the observed experimental residence-time distribution curves for the non-absorbable marker [14C]PEG 4000. The residence-time distribution analysis shows that the hydrodynamics of the perfusion solution within the jejunal segment in man is well approximated by a model containing on average between 1–2 mixing tanks in series. The solution is well mixed when using perfusion rates of 20, 30 and 60 mL min−. The average mean residence time estimates from the fitted residence-time distribution were 12 ± 7.6, 15 ± 4.2 and 7.7 ± 4.6 min, respectively, at these three perfusion rates. The mean volumes of the segment (Vs) were 25 ± 15, 45 ± 12 and 46 ± 27 mL, respectively. There were no statistical differences between 20, 30 and 60 mL min− in respect of the number of mixing tanks (n) and mean residence times.

This residence-time distribution analysis indicates that the luminal fluid in the Loc-I-Gut perfusion system is well-mixed, and that permeability calculations based on the well-mixed assumption most closely approximate the actual local (average) membrane permeability within the perfused segment.
Regional Intestinal Permeability in Rats of Compounds with Different Physicochemical Properties and Transport Mechanisms
Authors: Fagerholm Urban , Lindahl Anders , Lennernäs Hans
Published: April 2011

Because the absorption of orally administered drugs depends on intestinal permeability, we have investigated how absorptive capacity varies from the proximal to distal intestine in rats. The effective permeabilities of compounds with a range of physicochemical properties and different absorption mechanisms were estimated by use of a previously validated in-situ, single-pass perfusion model.

The low colonic permeabilities of d-glucose and l-dopa indicate the absence or low capacity of the glucose-and amino-acid-transporters in this region. With the exception of the small and moderately lipophilic nonsteroidal anti-inflammatory drug, naproxen, for which permeability was maintained throughout the intestine, the passive intestinal permeabilities for hydrophilic and lipophilic drugs were approximately twice as high in the jejunum and ileum as in the colon. These observations are in accord with those made in recent studies. However, the reasons for the high colonic permeability of non-steroidal anti-inflammatory drugs, and results obtained in previous animal experiments demonstrating that the colon is the region of the intestine with the highest absorptive capacity were not fully clarified.

These data show that the permeability to hydrophilic and lipophilic drugs decreases along the intestine, whereas it is maintained throughout the intestine for the small and moderately lipophilic naproxen. Further investigations are required to clarify the interplay between membrane composition, fluidity and permeability under various conditions in different absorption models.
Effect of Chitosan on Renal Function in Patients with Chronic Renal Failure
Authors: Jing Shi-Bing , Li Leishi , Ji Daxi , Takiguchi Yasuyuki , Yamaguchi Tatsuaki
Published: April 2011

The effects of chitosan have been investigated on eighty patients with renal failure undergoing long-term stable haemodialysis treatment.

The patients were tested after a control treatment period of 1 week. Half were fed 30 chitosan tablets (45 mg chitosan/tablet) three times a day. Ingestion of chitosan effectively reduced total serum cholesterol levels (from 10.14 ± 4.40 to 5.82 ± 2.19 mm) and increased serum haemoglobin levels (from 58.2 ± 121 to 68 ± 9.0 g L−). Significant reductions in urea and creatinine levels in serum were observed after 4 weeks of chitosan ingestion. The feeling of physical strength, the appetite and the sleep of patients in the treatment group had improved significantly after 12 weeks of ingestion, compared with those of patients in the control group. During the treatment period, no clinically problematic symptoms were observed.

These data suggest that chitosan might be effective treatment for renal failure patients, although the mechanism of the effect should be investigated further.
In-vivo Assessment of Extrahepatic Metabolism of Paeoniflorin in Rats: Relevance to Intestinal Floral Metabolism
Authors: Takeda Shuichi , Isono Tomoko , Wakui Yoko , Mizuhara Yasuharu , Amagaya Sakae , Maruno Masao , Hattori Masao
Published: April 2011

The extraction ratios of paeoniflorin in gut wall (EG), liver (EH) and lung (EL) were assessed by comparing AUCs after various routes of its administration to estimate the first-pass effects and the metabolism by intestinal flora.

Pulmonary extraction ratio of paeoniflorin was assessed by comparing AUCs calculated from venous and arterial plasma concentrations after its intravenous administration (0.5 mg kg−1). The mean pulmonary extraction ratio was estimated to be 006. The hepatic extraction ratio (EH was assessed by comparing AUCs after intraportal and intravenous administrations (0.5 and 5 mg kg−1). The plasma concentration profiles of paeoniflorin after intraportal administration were very close to those after intravenous administration, suggesting a negligible hepatic extraction ratio of paeoniflorin. The AUC value after intraperitoneal administration (0.5 mg kg−1) was greater than that after intraportal or intravenous administration. This finding suggests that paeoniflorin is not metabolized in the gut wall. The transference of paeoniflorin from the serosal side to the mucosal side was evaluated by the in-vitro everted sac method. The low intestinal permeability (194% at 60 min) was demonstrated by the comparison with phenobarbital (63.1% at 60 min).

We conclude that paeoniflorin is not metabolized by gut wall, liver and lung, its poor absorption from the intestine results in extremely low bioavailability and the unabsorbed fraction of paeoniflorin is degraded by the intestinal flora.
Effects of Oren-gedoku-to and Unsei-in, Chinese Traditional Medicines, on Interleukin-8 and Superoxide Dismutase in Rats
Authors: Wang L M , Yamamoto T , Wang X X , Yang L , Koike Y , Shiba K , Mineshita S
Published: April 2011

This study was conducted to elucidate the mechanisms of action of two Chinese traditional drugs, Oren-gedoku-to and Unsei-in, which have been used for many years in the treatment of inflammatory disorders.

In rats with acetic acid-induced inflammation, both drugs reduced interleukin-8 concentrations in the serum. Neither drug significantly affected superoxide dismutase activity in the serum, although Unsei-in increased superoxide dismutase activity in liver after 1 month of administration. Oren-gedoku-to showed no significant effect on liver superoxide dismutase activity.

It was considered that these medicines exert their anti-inflammatory effects mainly on the early stages of inflammation, wherein increased capillary permeability and migration of leucocytes occur.
Intestinal Brush-border Membrane Transport of Monocarboxylic Acids Mediated by Proton-coupled Transport and Anion Antiport Mechanisms
Authors: Tamai Ikumi , Takanaga Hitomi , Maeda Hiroshi , Yabuuchi Hikaru , Sai Yoshimichi , Suzuki Yuichi , Tsuji Akira
Published: April 2011

Intestinal brush-border membrane transport of monocarboxylic acids was investigated by using rabbit intestinal brush-border membrane vesicles (BBMVs) and isolated intestinal tissues mounted on Ussing-type chambers.

[3H]Mevalonic acid uptake by BBMVs showed an overshoot phenomenon in the presence of an inwardly directed proton gradient, but not in the presence of an inwardly directed sodium gradient or an outwardly directed HCO3− or chloride gradient. Initial uptake of mevalonic acid was saturable in the presence of a proton gradient. Uptake of [3H]mevalonic acid was inhibited by various monocarboxylic acids, including acetic acid, benzoic acid, lactic acid, nicotinic acid, pravastatin, salicylic acid and valproic acid, but not by dicarboxylic acid or amino acids. Acetic acid, which is transported by both anion antiport and proton-coupled transport systems, induced serosal bicarbonate-dependent alkalinization in the mucosal-side bathing solution of rabbit jejunal tissues, when examined in Ussing-type chambers. Pravastatin, which is a structural analogue of mevalonic acid and is absorbed via proton-coupled transport like mevalonic acid, did not. The result demonstrates that acetic acid is transported by the bicarbonate-dependent anion antiport system, whereas pravastatin is not.

So, it is suggested that monocarboxylic acids are transported by at least two independent transporters, namely, a proton-coupled transporter for most monocarboxylic acids, including mevalonic acid, pravastatin and acetic acid, and an anion antiporter for acetic acid, but not for mevalonic acid or pravastatin. Activation of anion antiporter can induce HCO3− secretion in intact intestine.
Pharmacological Activity of Feverfew (Tanacetum parthenium (L.) Schultz-Bip.): Assessment by Inhibition of Human Polymorphonuclear Leukocyte Chemiluminescence In-vitro
Authors: Brown Andrew M G , Edwards Carl M , Davey Michael R , Power J Brian , Lowe Kenneth C
Published: April 2011

The bioactivity of feverfew (Tanacetum parthenium) leaf extracts has been analysed, by use of a human polymorphonuclear leukocyte (PMNL) bioassay, to assess the relative contributions of solvent extraction and parthenolide content to the biological potency of the extract.

Extracts prepared in acetone-ethanol (system 1) contained significantly more parthenolide (mean ± s.d. 1.3 ± 0.2% dry leaf weight) than extracts in chloroform–PBS (phosphate-buffered saline; system 2; 0.1 ± 0.04% dry leaf weight) or PBS alone (system 3; 0.5 ± 0.1% dry leaf weight). Extract bioactivity, measured as inhibition of phorbol 12-myristate 13-acetate-induced, 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol)-enhanced PMNL chemiluminescence, followed a similar trend. Extracts inhibited phorbol 12-myristate 13-acetate-induced oxidative burst by amounts which, if solely attributable to parthenolide, indicated parthenolide concentrations for the respective solvent systems of 2.2 ± 0.6%, 0.2 ± 0.1% and 0.9 ± 0.1% dry leaf weight. The mean ratio of parthenolide concentration to the parthenolide equivalent/PMNl-bioactivity value, for acetone–ethanol and PBS extracts were both 1:1.7.

Parthenolide, although a key determinant of biological activity for T. parthenium leaf extracts based on the PMNl-bioassay, seems not to be the sole pharmacologically-active constituent. The identical and elevated bioactivity-parthenolide ratios for both organic and aqueous-phase leaf extracts suggest that a proportion of the other bioactive compounds have solubilities similar to that of parthenolide.
Studies on Amidated Pectins as Potential Carriers in Colonic Drug Delivery
Authors: Wakerly Zoë , Fell John , Attwood David , Parkins David
Published: April 2011

Amidated pectins have been assessed, in-vitro, for their potential value in colonic drug delivery. The monitoring of the release of a model soluble drug, paracetamol, gives a sensitive indication of the behaviour of the pectins under simulated gastrointestinal conditions.

Inclusion of calcium as a cross-linking agent increased the viscosities of amidated pectin gels to a maximum value. Further addition of calcium reduced gel viscosity and for pectin with a high extent of amidation this led to a reduction in drug release. Release was faster for pectin with less amidation in the presence of calcium; this could be related to matrix erosion.

The results of the study suggest that the materials might be of value in colonic delivery either alone or in combination, possibly in the form of a coating.
Possible Involvement of Protein Kinase C Inhibition in The Reduction of Phorbol Ester-induced Neutrophil Aggregation by Magnolol in the Rat
Authors: Wang Jih P , Lin Pei L , Hsu Mei F , Chen Chien C
Published: April 2011

The influence of the plant product magnolol on neutrophil aggregation has been investigated in the rat.

Magnolol inhibited phorbol 12-myristate 13-acetate (PMA)-activated rat neutrophil aggregation in a concentration-dependent manner with an IC50 (concentration resulting in 50% inhibition) of 24.2 ± 1.7 μM. Magnolol suppressed the enzyme activity of neutrophil cytosolic and rat brain protein kinase C (PKC) over the same range of concentrations at which it inhibited the aggregation. Magnolol did not affect PMA-induced cytosolic PKC-α and -δ membrane translocation or trypsin-treated rat-brain PKC activity, but attenuated [3H]phorbol 12,13-dibutyrate binding to neutrophil cytosolic PKC.

These results suggest that the inhibition of PMA-induced rat neutrophil aggregation by magnolol is probably attributable, at least in part, to the direct suppression of PKC activity through blockade of the regulatory region of PKC.
Interspecies Scaling: Predicting Volumes, Mean Residence Time and Elimination Half-life. Some Suggestions
Authors: Mahmood Iftekhar
Published: April 2011

Extrapolation of animal data to assess pharmacokinetic parameters in man is an important tool in drug development. Clearance, volume of distribution and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. Extensive work has been done to improve the predictive performance of allometric scaling for clearance. In general there is good correlation between body weight and volume, hence volume in man can be predicted with reasonable accuracy from animal data. Besides the volume of distribution in the central compartment (Vc), two other volume terms, the volume of distribution by area (Vβ) and the volume of distribution at steady state (Vdss), are also extrapolated from animals to man. This report compares the predictive performance of allometric scaling for Vc, Vβ and Vdss in man from animal data.

The relationship between elimination half-life (t 1/2) and body weight across species results in poor correlation, most probably because of the hybrid nature of this parameter. To predict half-life in man from animal data, an indirect method (CL = VK, where CL = clearance, V is volume and K is elimination rate constant) has been proposed. This report proposes another indirect method which uses the mean residence time (MRT). After establishing that MRT can be predicted across species, it was used to predict half-life using the equation MRT= 1.44 x t 1/2.

The results of the study indicate that Vc is predicted more accurately than Vβ and Vdss in man. It should be emphasized that for first-time dosing in man, Vc is a more important pharmacokinetic parameter than Vβ or Vdss. Furthermore, MRT can be predicted reasonably well for man and can be used for prediction of half-life.
Influence of Interfacial Rheological Properties of Mixed Emulsifier Films on the Stability of Water-in-Oil-in-Water Emulsions
Authors: Opawale Foyeke O , Burgess Diane J
Published: April 2011

The purpose of this study was to investigate the influence of mixtures of the emulsifiers Span 80, 83 and 85 and Tween 80 on multiple emulsion stability. An oscillatory ring-surface rheometer was used to measure interfacial elasticity at the oil-aqueous interface. Multiple emulsions were prepared via a two-step emulsification process and stability was evaluated by investigation of drug transport from freshly prepared and eight-day-old emulsions by use of a dialysis method. Photomicrography and droplet-size analysis of multiple emulsions were also conducted.

Spans 80 and 83 were appreciably elastic (683.10 ± 29.13 mNm−1 and 1128.09 ± 14.81 mNm−1, respectively at 5% w/v) when present at the mineral oil-aqueous interface whereas Span 85 and Tween 80 were not (11.10 ± 3.88 mNm−1 (5% w/v) and 0 (0.1–5% w/v) respectively). The interfacial elasticities of Spans 80 and 83 decreased in the presence of Tween 80 in the aqueous phase; this was attributed to co-adsorption of Tween 80 at the interface or aqueous-phase solubilization of the Spans within mixed micelles, or both. Drug-transport studies indicated that drug release on storage was lower from water-in-oil-in-water (w/o/w) emulsions prepared with 5% w/v Span 80 or 83 and 0.1% w/v Tween 80 than from emulsions prepared with 5% w/v Spans 80 or 83 and 1% w/v Tween 80. Photomicrography and droplet-size analysis indicated the same trend—emulsions containing a higher percentage of Tween 80 were less stable. The relatively stable w/o/w emulsions (e.g. 5% w/v Spans 80 or 83 and 0.1% w/v Tween 80) contained a large number of multiple droplets for up to eight weeks of storage whereas the relatively unstable w/o/w emulsions (e.g., 5% w/v Span 85 and 0.1% w/v Tween 80 and 5% w/v Spans and 1% w/v Tween 80) contained mostly simple droplets after only one week of storage. The mean volume/weight droplet size decreased on storage with breakdown of these w/o/w emulsions to simple oil-in-water emulsions.

There was a positive correlation between the interfacial elasticity and emulsion stability data. Mixed emulsifiers giving higher film strength, as quantified by interfacial elasticity measurements, resulted in more stable w/o/w emulsions.
Uptake of Fluoroquinolones in Human Monocytes Isolated from Peripheral Blood
Authors: Dorian Martine , Grellet Jean , Saux Marie C
Published: April 2011

The aim of this study was to develop a technique for separating monocytic cells in suspension from peripheral blood to measure the intracellular penetration of three fluoroquinolones (ofloxacin, ciprofloxacin and sparfloxacin).

Mononucleated cells were isolated from the blood on a density gradient with lymphoprep and purified by a specific technique of adhesion and disadhesion on fibronectin. The monocytes were obtained in suspension with 76.8% purity and 97.9% viability. This was a convenient form for measurement of intracellular accumulation by use of the velocity-centrifugation technique. Intra-monocytic penetration of ciprofloxacin, ofloxacin and sparfloxacin was measured at equilibrium after 30-min incubation in the presence of 16 μg mL−1 antibiotic. The results revealed low intra-monocytic accumulation of ciprofloxacin (intracellular-extracellular = 1.76) and ofloxacin (intracellular-extracellular = 1.42). The penetration of sparfloxacin was significantly higher (intracellular-extracellular = 2.4).

This study confirms the important differences between human immunocompetent cells in terms of their ability to concentrate quinolones. It also underlines the importance of monocyte-macrophage cellular differentiation as a determinant of antibiotic penetration.
Antioxidant and Hepatoprotective Activity of Punicalagin and Punicalin on Carbon Tetrachloride-induced Liver Damage in Rats
Authors: Lin C C , Hsu Y F , Lin T C , Hsu F L , Hsu H Y
Published: April 2011

Punicalagin and punicalin, isolated from the leaves of Terminalia catappa L., are used to treat dermatitis and hepatitis. Both compounds have strong antioxidative activity. The anti-hepatotoxic activity of punicalagin and punicalin on carbon tetrachloride (CCl4)-induced toxicity in the rat liver was evaluated.

Levels of serum glutamate-oxalate-transaminase and glutamate-pyruvate-trans-aminase were increased by administration of CCl4 and reduced by drug treatment. Histological changes around the liver central vein and oxidation damage induced by CCl4 also benefited from drug treatment.

The results show that both punicalagin and punicalin have anti-hepatotoxic activity but that the larger dose of punicalin induced liver damage. Thus even if tannins have strong antioxidant activity at very small doses, treatment with a larger dose will induce cell damage.
Statins therapy: a review on conventional and novel formulation approaches
Authors: Tiwari Radheshyam , Pathak Kamla
Published: April 2011

Background and objective

High levels of cholesterol lead to atherosclerosis, a factor predisposing to the development of coronary artery disease. Statin drugs, i.e. HMG-CoA reductase inhibitors, have been known since the end of the last century for their benefits against cardio- and cerebrovascular diseases and are widely used clinically. This review aims at compiling the research inputs being made for developing therapeutically efficacious dosage forms that have the potential to surmount the limitations of conventional dosage forms of statins.

Key findings

Statin drugs can reduce the endogenous synthesis of cholesterol and prevent the onset and development of atherosclerosis, and are therefore used as an effective treatment against primary hypercholesterolemia. At present, statin drugs are most often administered orally, on a daily basis. After administration, the bioavailability and the general circulation of statin drugs is fairly low due to the first-pass metabolism in the liver and clearance by the digestive system. Extensive pharmaceutical research in understanding the causes of low oral bioavailability has led to the development of novel technologies to address these challenges.

These technologies vary from conventional dosage forms to nanoparticulate drug-delivery systems, and have the potential to cause improvements in bioavailability and consequently therapeutic efficacy.
INDIVIDUAL DIFFERENCES IN REACTING TO DELAYED AUDITORY FEED‐BACK
Authors: BEAUMONT J. T. , FOSS B. M.
Published: April 2011

speech of normal subjects is impaired when subject hears himself speak a fraction of a second after uttering, that is, when auditory feed‐back is delayed. A study was made of individual differences in showing this impairment. It was found that those showing impairment in marked fashion were likely to have high scores in tests of other kinds of ‘perseveration’.
EXPERIMENTAL DESIGN: A CLOAK FOR INTELLECTUAL STERILITY
Authors: TAYLOR J. G.
Published: April 2011

Lewin's (1931) warning against applying in psychology the Aristotelian notion that frequency of occurrence is equivalent to lawfulness fell on deaf ears. To‐day Aristotelian modes of thought are as prevalent as ever, and are backed up by an elaborate structure of statistical methods and rules for experimental design. By reason of their logical tidiness these methods have the unfortunate effect of reducing (to a level below the threshold for effective action) the discontent that should be engendered by the rotten state of current psychological theory. What psychology needs is not statistical laws but scientific laws, that is, statements, expressed in general terms, that can generate specific predictions when specific values are assigned to the general terms. Such laws are unlikely to be found by statistical investigations, since they are concerned not with populations of systems but with single systems. Thus the law of gravitation is not a catalogue of the properties of solar systems, but it explains how any given solar system hangs together. It is argued that since mind occurs in an organic system its laws are likely to be laws of an ultrastable system (Ashby, 1952), and therefore not discoverable by statistical methods. Two kinds of investigation are required. The first is exemplified by Piaget's studies of the development of mind in individual children, and the second by Kohler's work with distorting spectacles. The first shows how the organism, considered as a multistable system, adapts itself by stages to its environment. The second involves a deliberate disorganization of both behaviour and perception, and enables us to observe simultaneously the processes of behavioural re‐adaptation and the correction of perceptual distortions. It is claimed that the results are compatible with the author's theory of the behavioural basis of perception.
THE ROLE OF THE REINFORCER AS A STIMULUS
Authors: REID R. L.
Published: April 2011

The reinforcing event is present as a stimulus in the situation in which a response is acquired and is absent from the extinction situation. When extinction conditions are made more similar to those of acquisition by introducing the reinforcer unrelated to behaviour (‘free’ reinforcement), the extinguished response is restored. Experiments with students, pigeons, and rata are described; and an analysis of the stimulus effects of reinforcement is used to account for ‘disinhibition’, ‘spontaneous recovery’, and speedy reconditioning after extinction.