bluuebunny/crossref_metadata_2025 huggingface dataset:
Discrimination between the functional and biochemical effects of two herbal oxytocics on the rat myometrium
Authors: Veale D J H , Du Preez J L , Havlik I , Oliver D W
Published: October 2002

This study on the rat myometrium is the first report where the effects of herbal extracts used as oxytocics in traditional medicine have been systematically analysed in the same preparation at the level of functional (contractile) and biochemical (second messenger generation) responses. Extracts of Agapanthus africanus and Clivia miniata (used in South African traditional medicine) were compared with other uterotonic agents with regard to their ability to stimulate phosphoinositide metabolism in the rat myometrium and cause accumulation of [3H]inositol phosphates. The maximal contractile response of the isolated rat myometrium in response to stimulation by the herbal extracts and agonists was compared with the maximal contractile response to cumulative addition of acetylcholine. The rank order of intensity of stimulation of [3H]inositol phosphate generation was: oxytocin > Agapanthus > prostaglandin F2α (PGF2α) > serotonin > acetylcholine > Clivia > ergometrine. This differed from the rank order of maximum contractile response: oxytocin > acetylcholine > PGF2α > serotonin ≅ Clivia > Agapanthus > ergometrine. Activity was also identified in chemical fractions of the plants and components common to both plants have been identified in the isolated active fractions. These results have identified that the uterotonic activity of Agapanthus is linked to increased turnover of phosphoinositides as a signal transduction mechanism, whereas this appears to play a less significant role in the uterotonic activity of Clivia. This study illustrates the benefits of using the measurement of stimulation of phosphoinositide metabolism as a bioassay in phytomedical research.
Inhibition of NF-κB-mediated gene transcription by the human A2B adenosine receptor in Chinese hamster ovary cells
Authors: Combes Patricia , Dickenson John M
Published: October 2002

NF-κB is a transcription factor that plays a vital role in regulating inducible gene expression in immune and inflammatory responses. In view of the well documented effects of adenosine on immune and inflammatory responses, we have explored whether adenosine A1, A2B and A3 receptors regulate NF-κB activity in transfected Chinese hamster ovary (CHO) cells using a luciferase reporter gene construct. No increases in NF-κB activity were observed in CHO-A1,-A2B and -A3 cells stimulated with the non-selective adenosine receptor agonist 5′-N-ethyl-carboxamidoadenosine. Elevating intracellular cyclic AMP (cAMP) levels using forskolin (direct activator of adenylyl cyclase) and rolipram (type IV, cAMP-specific phosphodiesterase inhibitor), inhibited NF-κB activity in CHO cells. Adenosine A2B receptor stimulation also inhibited NF-κB activity, whereas adenosine A1 and A3 receptor activation had no effect. These data reflect the known coupling of adenosine A2B receptors to increases in cAMP. In conclusion, adenosine A1, A2B and A3 receptors do not directly activate NF-κB in CHO cells. However, adenosine A2B receptor activation significantly inhibited NF-κB activity. Inhibition of NF-κB activity by the adenosine A2B receptor may contribute to the anti-inflammatory effects of adenosine.
Sustained ocular delivery of tilisolol to rabbits after topical administration or intravitreal injection of lipophilic prodrug incorporated in liposomes
Authors: Kawakami Shigeru , Yamamura Kenzo , Mukai Takahiro , Nishida Koyo , Nakamura Junzo , Sakaeda Toshiyuki , Nakashima Mikiro , Sasaki Hitoshi
Published: October 2002

To improve the retention time of tilisolol in the precorneal area or vitreous body, we prepared liposomes incorporating the O-palmitoyl prodrug of tilisolol. O-Palmitoyl tilisolol was completely incorporated in the liposomes. After topical administration of O-palmitoyl tilisolol liposomes to the rabbit eye, O-palmitoyl tilisolol rapidly disappeared from the tear fluid. The inclusion of 2% carmellose sodium slightly prolonged the retention of O-palmitoyl tilisolol in the tear fluid. After intravitreal injection of O-palmitoyl tilisolol liposomes, there was a relatively prolonged retention of O-palmitoyl tilisolol in the vitreous body. At 24 and 48 h after intravitreal injection of O-palmitoyl tilisolol liposomes, the tilisolol concentration in the vitreous body was significantly higher compared with the concentration after intravitreal injection of tilisolol liposomes.
Effects of furocoumarins from Cachrys trifida on some macrophage functions
Authors: Abad M J , de las Heras B , Silván A M , Pascual R , Bermejo P , Rodriguez B , Villar A M
Published: October 2002

Phytochemical and biological studies aimed at the discovery and development of novel antiinflammatory agents from natural sources have been conducted in our laboratory for a number of years. In this communication, three naturally occurring furocoumarins (imperatorin, isoimperatorin and prantschimgin) were evaluated as potential inhibitors of some macrophage functions involved in the inflammatory process. These furocoumarins have been tested in two experimental systems: ionophore-stimulated mouse peritoneal macrophages serve as a source of cyclooxygenase-1 and 5-lipoxygenase, and mouse peritoneal macrophages stimulated with E. coli lipopolysaccharide are the means of testing for anti-cyclooxygenase-2 and nitric-oxide-synthase activity. All above-mentioned furocoumarins showed significant effect on 5-lipoxygenase (leukotriene C4) with IC50 values of < 15 μM. Imperatorin and isoimperatorin exhibited strong-to-medium inhibition on cyclooxygenase-1- and cyclooxygenase-2-catalysed prostaglandin E2 release, with inhibition percentages similar to those of the reference drugs, indometacin and nimesulide, respectively. Of the three furocoumarins, only imperatorin caused a significant reduction of nitric oxide generation. Imperatorin and isoimperatorin can be classified as dual inhibitors, since it was evident that both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism were inhibited by these compounds. However, selective inhibition of the 5-lipoxygenase pathway is suggested to be the primary target of action of prantschimgin.
Chitosan: some pharmaceutical and biological aspects - an update
Authors: Singla A K , Chawla M
Published: October 2002

Chitosan, a natural polysaccharide, is being widely used as a pharmaceutical excipient. It is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Chitosan comprises a series of polymers varying in their degree of deacetylation, molecular weight, viscosity, pKa etc. The presence of a number of amino groups permit chitosan to chemically react with anionic systems, thereby resulting in alteration of physicochemical characteristics of such combinations.

Chitosan has found wide applicability in conventional pharmaceutical devices as a potential formulation excipient, some of which include binding, disintegrating and tablet coating properties. The polymer has also been investigated as a potential adjuvant for swellable controlled drug delivery systems. Use of chitosan in novel drug delivery as mucoadhesive, gene and peptide drug administration via the oral route as well as its absorption enhancing effects have been explored by a number of researchers.

Chitosan exhibits myriad biological actions, namely hypocholesterolemic, antimicrobial and wound healing properties. Low toxicity coupled with wide applicability makes it a promising candidate not only for the purpose of drug delivery for a host of drug moieties (anti-inflammatories, peptides etc.) but also as a biologically active agent.

It is the endeavour of the present review to provide an insight into the biological and pharmaceutical profile of chitosan. Various investigations carried out recently are reported, although references to research performed on chitosan prior to the recent reviews have also been included, where appropriate.
Skin delivery of 5-fluorouracil from ultradeformable and standard liposomes in-vitro
Authors: El Maghraby Gamal M M , Williams Adrian C , Barry Brian W
Published: October 2002

The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 μL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes, the non-rigid preparation was the best. However, stabilization of the liposome membrane with cholesterol abolished the benefit of this non-rigid preparation. It was concluded that ultradeformable vesicles are promising agents for skin delivery of drugs.
Application of Eudragit P-4135F for the delivery of ellagic acid to the rat lower small intestine
Authors: Jeong Young-Il , Yv̄ Rama Prasad , Ohno Tomoya , Yoshikawa Yukako , Shibata Nobuhito , Kato Shinichi , Takeuchi Koji , Takada Kanji
Published: October 2002

Based on the assumption that the delivery of ellagic acid to its site of action would show an antiinflammatory activity in inflammatory bowel disease (IBD), we have prepared microspheres using a new pH-sensitive polymer, Eudragit P-4135F (P-4135F), to deliver ellagic acid to the lower small intestine in rats. The microspheres were spherical in shape and the mean diameters were approximately 100–150 μm. The amount of ellagic acid released from the microspheres decreased by increasing the formulated amount of P-4135F. The release characteristics of ellagic acid were pH-dependent. By considering the factors loading efficiency and microsphere particle size distribution, ellagic acid-2 microspheres (P-4135F/ellagic acid = 1.65) were selected for further investigation. In a dissolution study, more than 95% ellagic acid was released within 0.5 h in pH 7.4 and 8.0 buffers. The release percent of ellagic acid was less than 40% in pH 6.8 and 7.0 and was less than 10% in pH 5.6 and 5.9. To observe the dissolution sites of the microspheres in the rat small intestine fluorescein was formulated in the microspheres as a tracer drug along with ellagic acid (50 mg kg−1). After intraduodenal administration of fluorescein-labelled microspheres to rats, the plasma fluorescein level started to increase at 0.5 h, by which time the microspheres had reached the middle part of the ileum. Microspheres started to dissolve within 1.0 h and the peak plasma fluorescein concentration was observed at 3.0 h, when the majority of the administered microspheres were dissolved in the terminal ileum. These results suggested that P-4135F microspheres could deliver ellagic acid to the lower part of the small intestine, and that the released ellagic acid would be distributed into the caecum and the ascending colon.
A simple, predictive, structure-based skin permeability model
Authors: Buchwald Peter , Bodor Nicholas
Published: October 2002

By an extension of our simple, molecular size-based model recently developed to describe octanol-water partition coefficients, we were able to obtain an entirely structure-based model that seems well suited to describe human skin permeability data. The corresponding equations not only eliminate the physicochemical interrelatedness of the parameters of the original Potts & Guy approach that was obtained from similar considerations, but also maintain its elegant simplicity and are consistent with a basic physicochemical model of the related phenomena. As the new model is structure based and fully computerized, it allows direct estimation of skin permeability for any molecule of known structure without the need to obtain octanol-water partition coefficients or other experimental data.
Prevention of structural perturbations and aggregation upon encapsulation of bovine serum albumin into poly(lactide-co-glycolide) microspheres using the solid-in-oil-in-water technique
Authors: Castellanos Ingrid J , Cuadrado Wanda L , Griebenow Kai
Published: October 2002

Bovine serum albumin (BSA) was encapsulated into poly(lactide-co-glycolide) (PLG) microspheres by a solid-in-oil-in-water (s/o/w) technique. We tested whether perturbations in BSA secondary structure could be minimized during encapsulation by using trehalose and how this would influence BSA aggregation and release. BSA secondary structure was monitored non-invasively by Fourier-transform infrared spectroscopy. When BSA was co-lyophilized with trehalose, lyophilization-induced structural perturbations were significantly reduced. The formulation obtained (BSA-Tre) was encapsulated into PLG microspheres and, by optimizing critical encapsulation parameters, a loading efficiency of 85% was achieved. However, due to the loss of the excipient in the o/w emulsion step, the structure of BSA-Tre was more perturbed than before encapsulation. Excipient-loss and encapsulation-induced structural perturbations could be prevented by saturating the aqueous phase in the o/w step with trehalose and by using the organic solvent chloroform. This in turn reduced the formation of soluble BSA aggregates. BSA was released from PLG microspheres using the improved formulations with an initial release in 24 h of not more than 22%, followed by a sustained release over at least 2 weeks. In summary, optimization of the encapsulation conditions in the s/o/w procedure resulted in the encapsulation of BSA without procedure-induced structural perturbations and minimized the release of aggregated protein. This demonstrates that the s/o/w technique is an excellent alternative to the most common encapsulation procedure, namely the water-in-oil-in-water technique.
Solid state properties of pure UC-781 and solid dispersions with polyvinylpyrrolidone (PVP K30)
Authors: Damian Festo , Blaton Norbert , Desseyn Herman , Clou Katrien , Augustijns Patrick , Naesens Lieve , Balzarini Jan , Kinget Renaat , Van den Mooter Guy
Published: October 2002

The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbo-thioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by co-evaporating UC-781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X-ray powder diffraction, and FT-IR spectroscopy. We investigated the single crystal structure of pure UC-781. The data from single crystal analysis showed that UC-781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be; a = 8.1556(7) Å, b = 17.658(2) Å and c = 23.609(2) Å; the unit cell was made up of eight molecules of UC-781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone-like structure. The data from X-ray powder diffraction showed that crystalline UC-781 was changed into the amorphous state by co-evaporating it with PVP K30. From differential scanning calorimetry analysis, UC-781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50% w/w. The data from FT-IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC-781 interacted with PVP K30 in solid dispersions through intermolecular H-bonding.
Synthesis of N-substituted 4,6-dioxo-imidazo[3,4-c] thiazoles and their analgesic activity in mice
Authors: Hugon Bernadette , Rubat Catherine , Coudert Pascal , Leal Fernand , Fialip Joseph , Couquelet Jacques
Published: October 2002

A new series of N-substituted dioxo-imidazo[3,4-c]thiazoles have been prepared and evaluated for their analgesic activity. The structures of these new derivatives were confirmed by IR, 1H NMR and 13C NMR spectra, and by elemental analysis. When administered intraperitoneally to mice all derivatives were devoid of any toxic effect, even at the high dose of 800 mg kg−1. In the phenylbenzoquinone-induced abdominal constriction test in mice, eight of the nine synthesized compounds exhibited significant antinociceptive properties with ED50 values (50% effective dose) ranging from 46.7 to 104.7 mg kg−1 intraperitoneally. Further investigation demonstrated that analgesic activity of the most effective derivatives 5e and 5f partly involved opioidergic and/or noradrenergic pathways.
Interaction of psychotropic drugs with monoamine oxidase in rat brain
Authors: Gnerre Carmela , Kosel Markus , Baumann Pierre , Carrupt Pierre-Alain , Testa Bernard
Published: October 2002

Literature observations indicate that some psychotropic drugs may have inhibitory activity towards monoamine oxidase (MAO). This study was undertaken to assess the potency, isozyme selectivity and mechanism of inhibition of representative first- and second-generation antidepressant drugs towards rat brain MAO-A and MAO-B. Five tricyclic antidepressants (imipramine, trimipramine, clomipramine, amitriptyline and doxepine) and three selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine and citalopram) were examined. They showed inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B (Ki in the micromolar range). Their mechanism of inhibition was competitive towards MAO-B and of a mixed competitive type towards MAO-A. The results suggest that some of the drugs examined might also contribute an MAO inhibitory effect in chronically treated patients.
Transport studies of insulin across rat jejunum in the presence of chicken and duck ovomucoids
Authors: Agarwal Vikas , Nazzal Sami , Reddy Indra K , Khan Mansoor A
Published: October 2002

Our aim was to evaluate the transport of insulin across rat jejunum in the presence of ovomucoids and to assess the effect of ovomucoids on intestinal tissue by studying the permeation of a lipophilic and a hydrophilic marker. Rat jejunal segments were mounted in a side-by-side diffusion chamber filled with Krebs bicarbonate buffer, bubbled with 95% O2/5% CO2 at a fixed flow rate and maintained at 37°C. The permeation of insulin, a lipophilic marker ([7-3H] testosterone) and a hydrophilic marker (D-[1-14C] mannitol) was evaluated in the presence of 0.5–1.5 μM duck ovomucoid (DkOVM) or chicken ovomucoid (CkOVM). For stability and permeation of insulin in the presence of α-chymotrypsin, an enzyme-to-inhibitor ratio of 1:1 and 1:2 was used. In the absence of α-chymotrypsin, the permeability coefficient (Papp) of insulin at pH 7.4 was 0.922 ± 0.168 times 10−7 cm s−1, which decreased with increasing concentrations of DkOVM or CkOVM. Conversely, the permeation of the hydrophilic and lipophilic marker increased with increasing concentrations of CkOVM and DkOVM. In stability studies, the percentage of drug remaining was found to be 2-fold higher at the 1:2 ratio than with the 1:1 ratio of enzyme to inhibitor. This was in agreement with the 2-fold increase in flux values of insulin in the presence of α-chymotrypsin and DkOVM at the 1:2 ratio of enzyme to inhibitor. The decrease in permeation of insulin in ovomucoids was unexpected. Marker transport studies indicated that ovomucoids have the potential to modulate transcellular and paracellular permeability. The flux enhancement of insulin in the presence of α-chymotrypsin and DkOVM is encouraging. The use of ovomucoids offers potential to enhance oral delivery of insulin and warrants further investigation.
Effects of Nicardipine on Collar-induced Intimal Thickening and Vascular Reactivity in the Rabbit
Authors: Kerry Zeliha , Yasa Mukadder , Akpinar Riyad , Sevin Gülnur , Yetik Günay , Tosun Metiner , Özdemir Necmettin , Erhan Yildiz , Üstünes Levent , Özer Asli
Published: October 2002

The effects of nicardipine treatment on collar-induced intimal thickening and on accompanying reactivity changes in rabbit carotid artery have been investigated.

Treatment for three weeks with subcutaneous nicardipine (20 mg kg−1 per day) significantly inhibited the intimal thickening caused by perivascular application of a silicone rubber collar. Potassium chloride (KCl), phenylephrine and 5-hydroxytryptamine (5-HT) induced concentration-dependent contractions in both sham-operated and collared arteries. Collar-induced attenuation of maximum KCl-, phenylephrine- and 5-HT-induced contraction was not affected by nicardipine. Collaring caused the means of pD2 values (the negative logarithm of EC50 values, 50% effective concentration) of 5-HT and phenylephrine to increase and decrease, respectively. Nicardipine did not affect the altered sensitivity to these agonists. Neither collar implantation nor nicardipine treatment altered the pD2 values for acetylcholine- and nitroglycerine-induced relaxations.

These results demonstrate that nicardipine inhibits collar-induced intimal thickening in rabbit carotid artery without affecting the accompanying changes in vascular reactivity, indicating a possible lack of association between the development of intimal thickening and altered reactivity.
Inhibition of Aromatase (P450Arom) by some 1-(Benzofuran-2-ylmethyl)imidazoles
Authors: Owen Caroline P , Nicholls Paul J , Smith H John , Whomsley Rhys
Published: October 2002

Studies of a series of 1-(benzofuran-2-ylmethyl)imidazoles, 1–5, previously proposed as potential agents for prostatic cancer by their inhibition of 17β-hydroxylase:17,20-lyase (P450 17), have been extended to their selectivity against placental microsomal aromatase (P450Arom) in man.

The compounds were 3–7-fold more potent than aminoglutethimide and had some selectivity for P450 17 as expressed by the ratio (IC50 P450Arom)/(IC50 P450) 17)/17.0 (2), 10.3(3), 34.6(4) and 42.0(5), where IC50 is the concentration resulting in 50% inhibition. The lower potency of 1–5 towards P450Arom compared with the racemic α-phenyl-substituted compounds (6, 80–1000 x aminoglutethimide) and some racemic α-methyl (8.5 and 12.2 x aminoglutethimide) and α-ethyl (12.1 and 32.9 x aminoglutethimide) analogues has been rationalized.

This work selectively extends studies of the P450 17 inhibitor 5, a potential prostatic cancer agent, towards other cytochrome P450 enzymes in the steroidogenic pathway and provides a general method for determining the relative influence of chemical manipulation of a parent inhibitor towards two enzymes in the pathway using additional literature data.
Diadenosine Polyphosphates in Cultured Vascular Smoothmuscle Cells and Endothelium Cells—Their Interaction with Specific Receptors and their Degradation
Authors: Verspohl E J , Johannwille B , Kaiserling-Buddemeier I , Schlüter H , Hagemann J
Published: October 2002

The role of diadenosine polyphosphates (ApnA, where “A” denotes “adenosine” and “n” denotes the number of phosphate groups “p”) as vasoconstrictors of smooth-muscle cells and as blood-pressure regulating and insulin-releasing compounds has been described. It was the aim of this study to investigate whether specific receptors for these compounds, mediating the above mentioned effects, occur in cultured vascular smooth-muscle cells (VSMC) and in endothelium cells, and whether these compounds are degraded during incubation.

Saturable binding sites for diadenosine polyphosphate [3H]Ap4A with an extremely quick saturation equilibrium, even at low temperature (4°C), are present in vascular smooth-muscle cells. Diadenosine polyphosphates at micromolar concentrations displaced [3H]Ap4A from binding sites; the ranking order was Ap4A γ Ap3A γ Ap5A ã Ap6A. Compounds interacting with purinergic P2x receptors such as suramin, α,β-methylene ATP and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS), albeit at high concentrations, displaced [3H]Ap4A from its binding sites. Surprisingly, at low concentrations the compounds tested increased the binding of [3H]Ap4A, which might imply the occurrence of positive receptor cooperativity or inhibition of [3H]Ap4A degradation. By use of thin-layer chromatography it was observed that [3H]Ap4A was quickly degraded (half-life approx. 12 min) in the extracellular medium to (mainly) adenosine and inosine. [3H]Ap4A and its degradation products were quickly taken up by the cells. Degradation can be inhibited by Ap6A, α,β-methylene ATP or PPADS. Rather similar degradation and uptake results were also obtained when endothelium cells were used.

These data indicate that specific binding sites for [3H]Ap4A are present in vascular smooth-muscle cells and that diadenosine polyphosphates at physiological concentrations displace binding. The receptors involved might be distinct diadenosine polyphosphate receptors, although the involvement of others, such as P2x receptors, is also possible. Ap4A is quickly degraded in the extracellular space and compounds that inhibit degradation result in an increase in [3H]Ap4A binding. It should be remembered that when diadenosine polyphos-phates are being investigated in physiological and pathophysiological studies of their impact on smooth-muscle cell proliferation and on vasoconstriction (blood-pressure regulation), results obtained from long-term incubations might be critical.
Pharmacological Characterization of KR-30988, a Novel Non-peptide AT1 Receptor Antagonist, in Rat, Rabbit and Dog
Authors: Lee Byung Ho , Lee Sung Ho , Jung Yi Sook , Seo Ho Won , Yoo Sung Eun , Shin Hwa Sup
Published: October 2002

The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin receptor antagonist, has been investigated by use of a variety of experimental models in-vitro and in-vivo.

KR-30988 inhibited the specific binding of [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a potency similar to that of losartan (IC50 values, the concentrations of drugs displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man (IC50 γ 10 μM for both drugs). Scatchard analysis showed that KR-30988 interacted competitively with recombinant AT1 receptor from man in the same manner as losartan. In functional studies with rat and rabbit aorta, KR-30988 non-competitively inhibited the contractile response to angiotensin II (pD2, = -log EC50 (where EC50 is the dose resulting in 50% of a reference contraction), 8.64 and 7.73, respectively) with a 20–85% decrease in the maximum contractile responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non-parallel shift to the right of the dose-pressor response curve to angiotensin II (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%, 0.09 mg kg−1) with a dose-dependent reduction in the maximum responses; in this antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan (ID50 1.74 mg kg−1). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (γ 24 h) anti-hypertensive effect; the potency was six times that of losartan (ED30 values, the dose reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg−1, respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (γ 8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mmHg, 1.04 and 7.96 mg kg−1, respectively).

These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.
An Investigation into the Erosion Behaviour of a High Drug-load (85%) Particulate System Designed for an Extended-release Matrix Tablet. Analysis of Erosion Kinetics in Conjunction with Variations in Lubrication, Porosity and Compaction Rate
Authors: Dürig Thomas , Venkatesh Gopadi M , Fassihi Reza
Published: October 2002

The effects of the amounts of lubricants (magnesium stearate 0–5% and talc 0–3%) and changes in compaction rate and tablet porosity on the mechanism of drug release from high drug-load controlled-release theophylline tablets have been examined.

Drug release was satisfactorily described by a surface-erosion model that takes into account the geometry of the tablet, differential radial and axial erosion rates, and the initial burst effect (r2 > 0.99 for all formulations). The axial and radial erosion rate constants were inversely proportional to the amount of magnesium stearate in the formulation (P < 0.0001). The most dramatic reductions in erosion rate occurred between 0 and 1% magnesium stearate content. For magnesium stearate concentrations ≥2.5% the ratio of radial to axial erosion rate constants was essentially constant at 3 (approx.); however, for formulations with magnesium stearate ≤1% the ratio tended toward unity. Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion rates. However, a threshold of 17% (approx.) porosity was identified below which further reductions in porosity resulted in only incremental changes in release rates. The rate of erosion and drug release was insensitive to changes in machine speed over the range 20 to 100 rev min−1.

For highly loaded matrix tablets containing sparingly soluble drugs, such as theophylline, magnesium stearate at appropriate levels can modulate the erosion rate constants and act as an effective release-controlling excipient. Drug-release profiles are predictable and relatively robust in terms of changes in compaction rate and applied force routinely encountered in large-scale tablet manufacturing.
Immunohistochemical and Functional Characterization of pH-dependent Intestinal Absorption of Weak Organic Acids by the Monocarboxylic Acid Transporter MCT1
Authors: Tamai Ikumi , Sai Yoshimichi , Ono Akihiko , Kido Yasuto , Yabuuchi Hikaru , Takanaga Hitomi , Satoh Eiko , Ogihara Takuo , Amano Osamu , Izeki Shoichi , Tsuji Akira
Published: October 2002

The participation of the monocarboxylic acid transporter MCT1 in the intestinal absorption of weak organic acids has been clarified by functional characterization, by use of stably transfected cells, and by immunohistochemical location of the transporter in intestinal tissues.

Immunohistochemical analysis by use of the anti-MCT1 antibody showed that MCT1 is distributed throughout the upper and lower intestines, especially in the basolateral membrane and, to a lesser extent, in the brush-border membrane. When the transporter gene rat MCT1 was transfected into MDA-MB231 cells, transport of benzoic acid, a model weak organic acid that has been generally believed to be transported across the cell membranes by passive diffusion, and lactic acid in rat MCT1-transfected cells was significantly increased compared with transport in cells transfected with the expression vector pRc-CMV alone (mock cells). The observed transport was pH-dependent and activity increased between pH 7.5 and pH 5.5, whereas pH-dependence in mock cells was moderate. Rat MCT1-mediated benzoic acid uptake was saturable, with an apparent Km value of 3.05 mM. In addition, MCT1 increased the efflux of [14C]benzoic acid from the cells. Several weak organic acids were also transported by rat MCT1.

These results show that pH-dependent intestinal absorption of weak organic acids, previously explained in terms of passive diffusion according to the pH-partition hypothesis, is at least partially accounted for by MCT1-mediated transport energized at acidic pH by utilization of the proton gradient as a driving force.
Effects of Cyclosporin on the Pharmacokinetics of Propranolol after Intravenous and Oral Administration to Control Rats and to Rats with Uranyl Nitrate-induced Acute Renal Failure
Authors: Lee Yong H , Ku Young S
Published: October 2002

The effects of cyclosporin on the pharmacokinetics of propranolol have been investigated after intravenous and oral administration of the drugs to control rats and to rats with uranyl nitrate-induced acute renal failure.

The effects of intravenous cyclosporin, 30 mg kg−1, on the pharmacokinetics of intravenous propranolol, 3 mg kg−1, were significant both in control rats and in rats with uranyl nitrate-induced acute renal failure; after intravenous administration of cyclosporin plasma concentrations of propranolol were significantly lower, the area under the plasma concentration-time curve (AUC) for propranolol from time zero to time infinity was significantly smaller, and the time-averaged total body clearance of propranolol was significantly faster. The effects of oral cyclosporin, 100 mg kg−1, on the pharmacokinetics of oral propranolol, 10 mg kg−1, were also significant, both in control rats and in rats with uranyl nitrate-induced acute renal failure; after administration of oral cyclosporin plasma concentrations of propranolol were significantly higher and the AUC of propranolol was significantly greater.

These data suggest that cyclosporin increases the elimination of propranolol, and that the first-pass effects of propranolol are reduced, or gastrointestinal absorption of propranolol is increased, or both, by cyclosporin.
Evaluation of the Anti-diabetic Property of Morinda lucida Leaves in Streptozotocin-diabetic Rats
Authors: Olajide Olumayokun A , Awe S Olubusayo , Makinde J Modupe , Morebise Olugbenga
Published: October 2002

The hypoglycaemic and anti-hyperglycaemic activities of a methanol extract of Morinda lucida Benth. (Rubiaceae) leaves were studied in normal and streptozotocin-diabetic rats.

In normal rats, the extract demonstrated a significant (P < 0.05) and dose-dependent hypoglycaemic activity within 4h after oral administration. The plasma glucose level of 400 mg kg−1 of the extract at 4h was 42.5 ± 0.4 mg/100 mL (control 67.4 ± 1.2 mg/100 mL). After 12h, the plasma glucose level of rats administered 50, 100, 200 or 400 mg kg−1 extract fell to 51.9 ± 1.2, 47.3 ± 0.8, 43.1 ± 0.4 and 40.0 ± 0.5 mg/100 mL, respectively. In hyperglycaemic rats, the extract produced a significant (P < 0.05) anti-diabetic effect from day 3 after oral administration, with 400 mg kg−1 extract-treated animals having a plasma glucose level of 248.7 ± 5.3 mg/100 mL compared with glibenclamide (10 mg kg−1)-treated animals with a plasma glucose level of 251.5 ± 5.8 mg/100 mL.

These results suggest that the leaves of Morinda lucida have a strong glucose lowering property when administered to streptozotocin-treated rats.
Optimization of a Dry Powder Inhaler Formulation of Nacystelyn, a New Mucoactive Agent
Authors: Vanderbist F , Wery B , Moyano-Pavon I , Moës A J
Published: October 2002

The aim of this study was to optimize a dry powder inhaler formulation containing a new mucoactive drug, nacystelyn. Formulations were made using three types of lactose, crystalline α-lactose, spray-dried lactose and a roller-dried anhydrous β-lactose. The roller-dried anhydrous β-lactose possessed the most adequate surface properties, resulting in a significantly higher (P < 0.05) in-vitro lung deposition of nacystelyn than the conventional crystalline α-lactose and spray-dried lactose. The particle size distribution of roller-dried α-lactose was optimized also. Within the size ranges tested (63–100, 90–125 and 100–160 μm), the coarser the lactose, the higher the in-vitro deposition of the drug (up to 40%). In contrast, the in-vitro lung deposition of 100–160 μm roller-dried β-lactose was very low (< 0.5%), so limiting the potential risk of lung irritation due to the carrier. The influence of the ratio of active ingredient/excipient (w/w) was also investigated. No difference was observed for mixtures from 1:2 to 1:4 while higher dilutions (1:5 and 1:6) showed significantly (P < 0.005) lower deposition results. Finally, the influence of the airflow rate was assessed. No dependence of the fine particle dose was observed between 40 and 80 L min−1 while significantly higher results were obtained at 100 L min−1.

The dry powder inhaler formulation of nacystelyn using the unusual roller-dried anhydrous β-lactose resulted in very high and reproducible in-vitro deposition results. However, the latter needs to be confirmed by in-vivo studies.
A parametric stability analysis of composite plates tapered in planform
Authors: Herdi M , Tutuncu N
Published: October 2002

The initial buckling load of flat trapezoidal plates of special orthotropy when loaded in axial compression is determined. Two types of boundary condition are considered: (a) the plate is clamped at one end and free on the other sides; (b) the plate is clamped along opposite ends and free along the sloping sides. The problem is twofold; determining the buckling load and providing a comprehensive parametric understanding of the buckling behaviour. An affine transformation scheme is infused into the solution process such that a minimum number of parameters remain. Using the potential energy functional, the problem of finding the buckling load is then solved by the finite element method. The results are presented for various rigidity ratios of the composite plates. It is observed that increasing the generalized rigidity ratio caused an increase in the stability of the plate.
Life assessment of weld repairs in 1/2Cr1/2Mo1/4V main steam pipes using the finite element method
Authors: Hyde T H , Sun W , Becker A. A
Published: October 2002

Weld repair at heavy section weldments is often a natural consequence following inspection of plant under high-temperature conditions. Four typical weld geometries and conditions have been studied: an ‘as new’ weld, a weld taken from plant after long-term service, a ‘full weld repair’ and partial repairs of two forms where repair was associated with either one or both weld interfaces. The parent material was 1/2CrMoV welded with 2CrMo weld metal and was removed from plant after 174 800 h operation. Material properties were obtained at 640 ° C and covered service-aged and new parent materials and weld metals. The heat-affected zone (HAZ) properties, as relevant to the weld models, were measured using indentation creep procedures. Realistic weld models were analysed using the finite element method and Norton's creep law. The expected lifetimes were found using peak representative rupture stresses in each zone, thereby taking account of the multi-axiality effects.

For the particular material data used in this investigation, results obtained have shown that the failure lives of fully and partially repaired welds are comparable with those of the service-aged weld and the failure lives of repaired welds are about half that of the new weld. The effects of changing the width of the weld metal region and of changing the axial (system) loading on the failure life and position of the new, aged and fully repaired welds were also considered. Finally, the validity of the finite element predictions of the failure life of weld repairs is discussed.
Numerical and experimental uniaxial loading on in-plane auxetic honeycombs
Authors: Scarpa F , Panayiotou P , Tomlinson G
Published: October 2002

Auxetic honeycombs show in-plane negative Poisson's ratio properties; they expand in all directions when pulled in only one, and contract when compressed. This characteristic is due to the reentrant shape of the honeycomb unit cell. The cell convoluteness gives a geometric stiffening effect that affects the linear elastic properties of the whole cellular solid. In this paper finite element simulations are carried out to calculate the in-plane Poisson's ratio and Young's moduli of re-entrant cell honeycombs for different geometric layout combinations (side cell aspect ratio, relative thickness and internal cell angle) subjected to uniaxial loading. The results show a high sensitivity of the mechanical properties for particular ranges of the geometric cell parameters. An image data detection technique is used to extract displacements and strains from an aramid paper re-entrant honeycomb sample in a tensile test. The comparison between numerical and experimental results shows good agreement.
Factors influencing the elastic stability of orthotropic plates containing a rectangular cut-out
Authors: Brown C. J , Yettram A. L
Published: October 2002

A parametric study of the elastic buckling loads for rectangular orthotropic plates with square or rectangular cut-outs has been carried out. The effect of cut-out size, cut-out location and orientation of principal material directions were all investigated, as well as the effects of changing the material modular ratio and shear modulus. Simply supported and fully fixed boundaries were both considered. The analyses employed the conjugate load-displacement method for elastic instability analysis applied to element discretization of the plates.

The main conclusion from this work was confirmation that the presence of a hole could equally well raise the elastic critical load just as much as lower it, depending on the hole size, shape and location and also the aspect ratio of the plate. From the viewpoint of material properties, it was found that the shear modulus, an independent property for orthotropic materials, has a major influence on the critical load.
Strain concentration factor of notched cylindrical bars under tension creep
Authors: Majima T , Liu Q
Published: October 2002

Variations in the new strain concentration factor (SNCF) with creep deformation have been studied for notched cylindrical bars. This new SNCF is based on the average axial strain, defined under the triaxial state of stress at the net section. The uniaxial creep constitutive equations employed in the finite element calculations are primary-tertiary, primary-secondary and tertiary creep. With creep deformation the new SNCF increases sharply from its elastic value and reaches a maximum. After that it gradually decreases from the maximum with creep deformation. The new SNCF decreases at any deformation level as the notch radius increases. However, it never becomes less than unity. The notch radius has the strongest effect on the SNCF from infinitesimal to large deformation. The difference in the type of creep constitutive equation has an effect on the SNCF only beyond the deformation level at the maximum SNCF. Creep deformation provides the pattern of the variation, i.e. an increase in the SNCF up to the maximum and subsequent gradual decrease. The conventional SNCF becomes less than unity after increasing from its elastic value to a maximum and then decreasing. The fact that the conventional SNCF is less than unity is contradictory to the concave distributions that the axial strain has on the net section at any deformation level. The new SNCF provides reasonable values, which are consistent with the concave distributions.
Structural integrity of a welded attachment junction: Analysis and collapse tests
Authors: Gray T G F , Mackenzie D , Heaton A , Lubis A
Published: October 2002

The aim of the research described was to establish a sound structural analysis procedure for load-carrying fillet-welded attachments with particular reference to cases where the welds are well separated by crack-like discontinuities. Finite element analysis (FEA) was used to determine linear elastic fracture mechanics stress intensities and limit states for a range of typical attachment geometries, on the assumption that these two failure conditions represent practical extremes of behaviour. The influence of differences between the yield strengths of the parent materials and the welds was explored in the theoretical study. The results of the FEA were analysed to obtain the development of appropriate design/assessment formulae, based on simple structural mechanics models. These formulae provide an approach that improves on current codes of practice, which treat the loads on welds as statically determinate and ignore crack-related failure potential. Collapse tests were carried out on two-dimensional models of the cases studied. These included specimens where the strength properties were uniform throughout and others where higher-yield-strength welds were incorporated. The results confirmed the FEA results and associated formula with respect to the limit state and provided some insight into the effects of heterogeneous strength properties in the junction.
Measurement of residual stresses in beams and plates using the crack compliance technique
Authors: Nowell D , Tochilin S , Hills D. A
Published: October 2002

The crack compliance method provides a useful extension to the range of techniques available for the measurement of residual stress fields. The method is most suitable for simple geometries where the stresses vary in one direction only (e.g. usually depth). This paper describes the application of the dislocation density method to the calculation of the compliance functions required for the analysis of experimental data (the surface strain changes as a slot is cut). In particular, the kernel functions appropriate to a specimen of finite thickness (i.e. a beam or a plate) are given. The use of the technique for this geometry, including the use of multiple strain gauges, is discussed. Some sample results are given for the case of a plastically bent beam and these are compared with predictions from beam theory and with neutron diffraction measurements.
Measurement and prediction of residual stresses in thick-section steel welds
Authors: Smith D. J , Bouchard P J , George D
Published: October 2002

Significant levels of residual stress are developed in the production of thick-section steel welds. Residual stress can be measured by a variety of methods, although few offer the ability to determine the spatial distribution completely through the thickness. This paper summarizes recent developments in the deep-hole method for measuring residual stresses in thick-section welds. Experimental results obtained from a variety of welded steel components are described. The measurement method has also been used to provide validation for finite element simulations of residual stresses in a welded cylinder-to-nozzle stainless steel component. The paper describes the finite element weld analysis and compares the results with measurements obtained from several locations in the complex geometry. Overall, there is good agreement between the predicted and measured distributions of residual stress, but the magnitudes of predicted stress tend to be greater.
Effects of residual stresses on fracture behaviour—experimental results and assessment methods
Authors: Ainsworth R. A , Sharples J. K , Smith S. D
Published: October 2002

The influence of residual stresses on fracture behaviour depends on the level of plasticity in a component. Under predominantly elastic conditions, residual stresses can significantly reduce the load-carrying capacity of a defective structure. Conversely, the effects of residual stresses can be minimal when plasticity is widespread. In this paper, a set of experiments with well-characterized residual stresses is used to demonstrate these effects. A new method for assessing defects in practical structures with residual stresses is then described and related to existing methods. The method is applied to the experimental data and shown to be generally accurate and yet conservative.