bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Backing Materials and Multilayered Systems on the Characteristics of Bioadhesive Buccal Patches
Authors: Guo Jian-Hwa , Cooklock K M
Published: April 2011

The effects of backing materials (ethylcellulose, polyvinylpyrrolidone and cellulose acetate mixture, and poly(ethylene-co-vinyl acetate) on the characteristics (hydration and adhesion) of newly developed bioadhesive patches for controlled drug delivery via the buccal mucosa were investigated.

It was found that the swelling profiles of buccal patches were changed dramatically by the species and amount of the backing materials, and those changes could alter the drug release profile. The drug release profiles of single-layered and multilayered buccal patches were significantly different.

It was demonstrated that the multiple-layer device could be used to modify the drug release for obtaining the ideal clinical pharmacokinetic release profile.
Pharmacological Characterization of the Vanilloid Receptor in the Rat Isolated Vas Deferens
Authors: Wardle Kay A , Furey Genevive , Sanger Gareth J
Published: April 2011

The present study set out to further characterize the vanilloid receptor in the rat isolated vas deferens.

In this preparation, both capsaicin and resiniferatoxin (RTX) evoked a concentration-dependent inhibition in the amplitude of electrically-evoked contractions with pEC50 values of 7.62 ± 0.03 and 12.2 ± 0.21 respectively. Responses to capsaicin were fast in onset and faded rapidly over a 30-min exposure period, whereas those to RTX were slow in onset and well maintained, an observation believed to reflect pharmacokinetic differences in the rate of penetration to the vanilloid receptor. Responses to both agonists showed mutual cross-desensitization and were antagonized by both the vanilloid-receptor antagonist capsazepine and the ion-channel blocker ruthenium red. The capsaicin analogue, olvanil failed to either mimic or antagonize capsaicin-evoked responses in the rat isolated vas deferens, an effect at variance with previous observations in other tissues.

The reason for these differences is unclear, but the possibility of multiple classes of receptor cannot at this stage be ruled out.
Effects of Sulpiride and Nemonapride, Benzamide Derivatives Having Distinct Potencies of Antagonistic Action on Dopamine D2 Receptors, on Sensitization to Methamphetamine in Mice
Authors: Kuribara Hisashi
Published: April 2011

The acute ambulatory stimulation by methamphetamine (2 mg kg−1 s.c.) was dose-dependently reduced by 3-h pretreatment or combined treatment with sulpiride (1–100 mg kg−1 s.c), and combined treatment with nemonapride (0.003-0.03 mg kg−1 s.c), benzamide derivatives having selective antagonistic action on dopamine D2 receptors. The repeated (5 times) administrations of methamphetamine at 3-day intervals induced a sensitization to its ambulation-increasing effect, and the sensitization was significantly inhibited by 3-h pretreatment with either sulpiride (10–100 mg kg−1), or combined treatment with either sulpiride (3 or 10 mg kg−1) or nemonapride (0.01 or 0.03 mg kg−1) at each methamphetamine administration. Although the ambulation-increasing effect of methamphetamine disappeared by 3 h after the administration, the 3-h post-treatment with sulpiride (3 mg kg−1) or nemonapride (0.03 mg kg−1) after each methamphetamine administration was effective for a significant inhibition of the induction of methamphetamine sensitization, whereas, the comparatively higher doses of sulpiride (30 and 100 mg kg−1 in the combined treatment, and 10–100 mg kg−1 in the post-treatment) did not inhibit the methamphetamine sensitization. On the other hand, the repeated administrations of sulpiride (30 and 100 mg kg−1) alone, but not any doses of nemonapride, at 3-day intervals elicited a significant increase in the sensitivity to methamphetamine.

These results suggest that, although the potencies of the anti-methamphetamine effects of sulpiride and nemonapride differ by a factor of 3000, they inhibit the induction of sensitization to methamphetamine in the pretreatment, combined treatment and early post-treatment schedules. However, it is also suggested that the repeated treatment with comparatively higher doses of sulpiride may produce a denervation supersensitivity of dopamine D2 receptors, and resultant increase in the sensitivity to methamphetamine.
Synthesis, Gastroprotective, Antisecretory and Anti-helicobacter Effect of N-[3-(3-(1-Piperidinylmethyl) phenoxy)propyl]-hydroxyacetamide 2-Hydroxypropane-1,2,3-tricarboxylate Bismuth (3+) Complex (MX1)-MX1
Authors: Ivanov C , Petkov O , Petrov P , Taskov M , Athanassova R , Tsvetkova E , Kotsev V , Lyutakov G , Nikolov G , Savov E
Published: April 2011

MX, (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide 2-hydroxypropane-1,2,3-tricar-boxylate bismuth (3+) complex) is a novel salt of the active metabolite of H2-antagonist roxatidine with a complex of bismuth with citric acid.

In a model of ethanol-induced ulcers in male Wistar rats, both roxatidine and the bismuth salt reduced the number and the total length of lesions. Comparison of roxatidine and MX, at equimolar doses of 160 μmol kg−1 showed a more potent cytoprotective effect of MX1. The potency of anti-secretory and antiacidic effects of MX1 was more than twice that of roxatidine on histamine-stimulated secretion in female Wistar pylorus-ligated rats. Microbiological tests with the reference bismuth preparation De-Nol showed prominent anti-Helicobacter properties of MX1 in-vitro. Both test compounds had similar range of MICs to Helicobacter pylori, from 4 to 64 μg bismuth mL−1.

The cytoprotective, antisecretory, anti-acidic and anti-Helicobacter properties of the new agent MX1 warrant further more extensive pharmacological and clinical trials.
A Novel Method for the Preclinical Assessment of Rectal Irritation
Authors: Kinouchi Yoshihito , Takeichi Yoh'ichiro , Yata Noboru
Published: April 2011

The purpose of this study concerns a novel method for preclinical assessment of rectal irritation caused by suppositories introduced into the rectum. Rectal irritation was assessed by the balloon method in fasting conscious rats. This method is based on measuring rectal contractions due to possible irritation caused by the presence of drugs and adjuvants in the suppository.

In control experiments (vehicle only), significant rectal contractions were not observed in a range of pH 1.5–11.0 and osmotic pressure 70–2000 mOsm kg−1 H2O, respectively. On the other hand, strong contractions were observed after rectal administration of an aqueous solution of 50% glycerin, 100 mm sodium caprate or 25 mm sodium cholate. The intensity of contraction after rectal administration of sodium caprate or sodium cholate was dependent on the concentration in the dosing solution. In addition, the effect of sodium caprate and sodium cholate on rat rectal mucosa was investigated by optical light microscopy. Although slight or moderate alteration such as the presence of mucinous substance in lumen and congestion, oedema and haemorrhage of the rectal membrane 20 min after rectal administration, there was no major damage to the rectal mucosa. There was a correlation between the median score for mucinous substance in lumen and mean intensity of rectal contraction. For comparative purposes, defecating sensations, pain, itch, burning sensations, and awareness of the presence of a foreign body after administration of suppositories containing 0, 1, 2 and 4% sodium caprate were examined in eight healthy volunteers. The defecating sensation in the human subjects correlated with the intensity of rectal contraction in rats.

The results suggest that rectal contraction in conscious rats could be a useful index for prediction of a defecating sensation in man.
Characterization of Surfactant Effect on Aggregates in Model Aerosol Propellent Suspensions
Authors: Bower Christopher , Washington Clive , Purewal T S
Published: April 2011

A novel technique of rheometry combined with image analysis to study model aerosol suspensions used in inhalation technology has been used. The role of surfactants in the stability and aggregation of such suspensions was also investigated.

Addition of increasing concentrations of sorbitan monooleate (Span 80) to suspensions of micronized polar solids in model CFC suspensions caused marked changes in aggregate morphology and suspension stability. The aggregate behaviour was characterized in a modified constant stress rheometer by use of image analysis techniques, allowing the measurement of particle size, elongation and fractal dimension as a function of shear stress.

This method was used to study the effect of Span 80 on suspensions of lactose and salbutamol sulphate in P113. Lactose suspensions showed a gradual reduction in aggregate size, and more spherical structure, with increasing surfactant concentration. Salbutamol sulphate suspensions displayed a more prominent transition from an aggregated state to a weakly aggregated state at 0.02% w/w surfactant. Both suspensions were disaggregated by shear, the resulting fractal properties of the aggregates in shear demonstrating the increased particle mobility caused by the surfactant.
Pharmacokinetic and Pharmacodynamic Properties of FK070 (KDI-792), A Novel Thromboxane Receptor Antagonist/Thromboxane Synthetase Inhibitor, After Single and Multiple Oral Administrations to Healthy Volunteers
Authors: Uematsu T , Kosuge K , Umemura K , Nakano M , Terakawa M , Nakashima M
Published: April 2011

FK070, a thromboxane A2 (TXA2) receptor antagonist/TXA2 synthetase inhibitor, was given orally to healthy male volunteers in a single-and multiple-dose study.

In the single-dose study (200, 300, 400 mg), the area under the plasma concentration—time curve (AUC) and the maximum plasma concentration (Cmax) increased non-linearly with dose, while the mean elimination half-life (t1β) was essentially unchanged (3.9-7.3 h). Recovery of the unchanged drug in the urine was 12–25%. Cmax and AUC as determined with 200 mg of drug after a meal decreased by about 60 and 30%, respectively. Ex-vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was almost completely inhibited within 1 h, after all doses of drug, with a significant dose-dependent inhibition maintained for 8 h or more, which was much longer than was expected from drug plasma concentration. The aggregation by adenosine diphosphate (ADP) was inhibited to a lesser extent. FK070 also inhibited TXA2 synthetase as evidenced by decreased production of TXB2 and reciprocally increased production of 6-keto-prostaglandin F1α in the serum during ex-vivo whole blood coagulation. These effects peaked 1 h after drug and lasted until 4 h with the higher doses.

In the multiple-dose study (300 mg, twice a day, after meals for 6.5 days), drug concentrations in the plasma were well fitted to a three-compartment open model with first-order absorption. FK070 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, with a significant inhibition lasting as long as 48 h after conclusion of administration.

No clearly drug-related changes were found in routine laboratory tests, subjective and objective findings, or vital signs.

FK070 was concluded to be well tolerated and to provide long-lasting blockade of TXA2 receptors, and plasma concentration-dependent inhibition of TXA2 synthetase in the platelets.
Neural Involvement in 5-Hydroxytryptamine-induced Net Electrogenic Ion Secretion in the Rat Intestine In-vivo
Authors: Franks C M , Hardcastle J , Hardcastle P T
Published: April 2011

5-Hydroxytryptamine (5-HT) induces active electrogenic anion secretion by both the small intestine and the colon, responses that can be detected from measurements of transmural electrical activity. This approach was adopted to examine the involvement of neural mechanisms in 5-HT-induced secretion in rat proximal jejunum, distal ileum and proximal colon in-vivo.

Under control conditions, 5-HT caused maximum rises in transintestinal potential difference of 4.7 ± 0.3, 3.8 ± 0.4 and 7.6 ± 0.3 mV, respectively, with corresponding ED50 values of 28 ± 3, 38 ± 4 and 41 ± 4 nmol kg−1 (n = 12). In each region examined a neural component in the secretory response to 5-HT was identified. Hexamethonium (22 μmol kg−1) reduced the 5-HT response in each region; in the jejunum and colon, it also attenuated the responses to the 5-HT3 agonist, phenylbiguanide and to 5-methoxytryptamine (5-MeOT), an agonist at all 5-HT receptors except 5-HT3, indicating that in these regions the nicotinic pathway can be activated by more than one 5-HT receptor subtype. Atropine (0.27 and 2.7 μmol kg−1) was found to have regional effects on the intestinal responses to 5-HT receptor agonists. In the jejunum, evidence for a pro-secretory muscarinic pathway which could be activated by more than one 5-HT receptor subtype was found. In the ileum and colon no muscarinic pro-secretory pathway was identified, indeed in the colon, an anti-secretory pathway may be present. This muscarinic anti-secretory pathway was observed with phenylbiguanide and 5-MeOT, but not 5-HT. Substance P release does not appear to be involved in mediating the intestinal secretory response to 5-HT.

5-HT-induced intestinal anion secretion may involve a direct secretory action on the enterocyte which can be modified by neurally-mediated pro-secretory and anti-secretory pathways, the balance between these processes varying down the length of the gut.
Catalepsy Induced by Manidipine, a Calcium Channel Blocker, in Mice
Authors: Haraguchi Kaori , Ito Kiyomi , Sawada Yasufumi , Iga Tatsuji
Published: April 2011

Manidipine, a calcium channel blocker, is a piperazine derivative similar to flunarizine or cinnarizine, which are known to induce parkinsonism. Since it has been reported that manidipine can worsen parkinsonian symptoms in a patient with Parkinson's disease, we have evaluated catalepsy in manidipinetreated mice and compared this with flunarizine-and haloperidol-induced catalepsy.

The minimum dose at which manidipine induced catalepsy was 200 times higher than that of haloperidol whereas for flunarizine, the minimum dose was 50 times higher than that for haloperidol. Manidipine, flunarizine and haloperidol occupied both dopamine D1 and D2 receptors, and D2-receptor occupancy was higher than D1-receptor occupancy.

These results suggest that the blockade of dopamine D1 and D2 receptors by drugs and the drug-induced catalepsy are related to the structure (piperazinyl substituent) of the drugs.
Cholesterol-fed Rabbits: Study of the Response of the Vas Deferens to Adrenergic and Non-adrenergic Stimulus and to a K-Opioid Agonist
Authors: Alfaro M J , Ormazábal M J , García-Arroba L , Martín M I
Published: April 2011

The aim of the present study was to analyse the contractility of the isolated vas deferens from hypercholesterolaemic rabbits; for this purpose we evaluated the contractile response induced by noradrenaline and by electrical stimulation.

A significant increase in the amplitude of adrenergic and non-adrenergic responses was observed in vas deferens from hypercholesterolaemic rabbits.

These data suggest an increase in the contractility of the smooth muscle in these animals.
Effects of the Anticancer Agent Vinorelbine on Endothelial Cell Permeability and Tissue-factor Production in Man
Authors: Mouchard-Delmas Corine , Devie-Hubert Isabelle , Dufer Jean
Published: April 2011

Because antineoplastic drugs could increase endothelial blood barrier permeability and thrombotic diseases have been described as a complication of treatments with vinca alkaloids, the effect of a therapeutic dose (10-8 M) of vinorelbine on transendothelial permeability was analysed by measuring the movement of albumin across a monolayer of human venous endothelial cells.

Induction of procoagulant activity was assessed by evaluation of tissue-factor activity in cell lysates. Vinorelbine increased the permeability of endothelial cells after 3 h of culture, as observed with thrombin. In addition, thrombin induced strong tissue-factor activity, a phenomenon not observed after vinorelbine treatment.

These data suggest that vinorelbine could modulate endothelial barrier permeability. This effect is not linked to an increase in tissue-factor activity, suggesting that their induction could operate through separate pathways.
Cytokine-mediated Inhibition of Erythropoietin Synthesis by Dexamethasone
Authors: Leng H M J , Kidson S H , Keraan M M , Randall G W , Folb P I
Published: April 2011

The effect of inflammatory cytokines on the in-vitro synthesis of erythropoietin by HepG2 cells was evaluated.

Monocyte-conditioned medium, and the cytokines interleukin-1β, interleukin-6 and tumour necrosis factor-α all reduced synthesis of erythropoietin. The steroidal anti-inflammatory drug, dexamethasone, did not affect cytokine-mediated erythropoietin inhibition. Dexamethasone did cause a reduction in the secretion of erythropoietin inhibitory cytokines from monocytes.

These results point to a possible therapeutic approach in the treatment of anaemia caused by suppression of erythropoietin synthesis by monocytic cytokines.
Novel Sources of Mammalian C-S Lyase Activity
Authors: Adcock Harriet J , Gaskin Peter J , Shaw P Nicholas , Teesdale-Spittle Paul H , Buckberry Lorraine D
Published: April 2011

The C-S lysis of L-cysteine conjugates is one biotransformation pathway which is responsible for the generation of mutagenic and cytotoxic metabolic species. Thirteen cysteine S-conjugates were synthesized in our laboratories and incubated with aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) enzymes from porcine heart tissue. The C-S lyase (CSL) activity for each enzyme-substrate combination was determined.

ASAT and ALAT were shown to exhibit CSL activity and it was also demonstrated that this activity was inhibited in the presence of the pyridoxal phosphate-dependent enzyme inhibitor amino(oxyacetic acid) confirming the pyridoxal phosphate-dependent mechanism by which C-S lysis is known to take place. This finding has potentially important implications for the risk assessment of compounds which produce L-cysteine conjugates during their biotransformation.
Synthesis of α-Glucosidase I Inhibitors Showing Antiviral (HIV-1) and Immunosuppressive Activity
Authors: van den Broek L A G M , Nieuwenhof M W P Kat-Van Den , Butters T D , Van Boeckel C A A
Published: April 2011

The synthesis of a series of analogues of the monosaccharide α-glucosidase I inhibitor N-decyl-1-deoxynojirimycin (1) is described. With the incorporation of a single oxygen atom particularly at position seven in the N-decyl side chain, i.e. to give N-7-oxadecyl-dNM (4), the therapeutic ratio (α-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. N-7-Oxadecyl-dNM inhibits purified porcine liver α-glucosidase I with an ***IC50 value of 0.28 μM. The position of the oxygen atom in the N-decyl side chain is of importance since N-3-oxadecyl-dNM is less active and, moreover, is toxic to HepG2 cells at 3 μM. Subsequently, the synthesis of a disaccharide inhibitor of α-glucosidase I is described. The aminodisaccharide ManNH2α1,2Glc*** (12) inhibits α-glucosidase I with an IC50 value of 15ṁ7 μM. Two closely related monosaccharide derivatives of 12 did not inhibit the enzyme at low μM concentrations (no inhibition at 5 μM), showing the additional effect of binding of the aglycon fragment of the molecule to the active site of α-glucosidase I. Next, the N-alkyl-dNM derivatives were analysed for antiviral and immunomodulatory activity in-vitro. It is found that the most potent α-glucosidase I inhibitor from this study, N-7-oxadecyl-dNM (4) inhibits HIV-1 induced syncytia formation and lymphocyte proliferation in-vitro. Finally, compound 4 was also investigated in-vivo. N-7-Oxadecyl-dNM (4) reduced adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.
Preliminary Synthetic Studies of Methyllycaconitine, a Potent Nicotinic Acetylcholine Receptor Antagonist: Rapid Syntheses of AE-Bicyclic Analogues
Authors: Coates Philippa A , Blagbrough Ian S , Rowan Michael G , Pearson David P J , Lewis Terence , Potter Barry V L
Published: April 2011

A series of bicyclic analogues incorporating the homocholine motif of methyllycaconitine has been prepared to test the hypothesis that this is the essential pharmacophore of this potent, selective nicotinic receptor antagonist. A double Mannich reaction has been employed to construct the 3-azabicyclo[3.3.1]-nonane ring system, containing an N-ethylpiperidine moiety. The neopentyl-like alcohol was then esterified, using isatoic anhydride under basic conditions, to afford the corresponding anthranilate.
A Dapsone-induced Blood Dyscrasia in the Mouse: Evidence for the Role of an Active Metabolite
Authors: Ahmadi M , Khalaf L F , Smith H J , Nicholls P J
Published: April 2011

In the female mouse, dapsone (50–500 mg kg−1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0ṁ5-1 h with recovery to baseline values occurring by 4h. Cimetidine (100 mg kg−1, p.o.), a known inhibitor of several hepatic P450 isozymes administered 1 h before dapsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formation in mouse erythrocytes and cytotoxicity to human mononuclear leucocytes. In both instances, the toxic effects were markedly reduced by cimetidine. Daily dosing of mice with dapsone (50 mg kg−1, p.o.) for 3 weeks induced a blood dyscrasia, characterized by a fall of platelet and white blood cell counts, which was inhibited by cimetidine (100 mg kg−1, p.o. daily).

It is concluded that an active metabolite of dapsone arising from a P450-dependent pathway is involved in the genesis not only of the methaemoglobinaemia but also the blood dyscrasia arising from repeated administration of the drug in this species.
Comparison of the Intestinal Secretory Response to 5-Hydroxytryptamine in the Rat Jejunum and Ileum In-vitro
Authors: Hardcastle J , Hardcastle P T
Published: April 2011

A secretory response to 5-hydroxytryptamine (5-HT) is observed throughout the intestinal tract; this investigation has compared the nature of this response in the jejunum and ileum of the rat in-vitro.

Different basal electrical activity was observed for jejunal and ileal sheets of rat small intestine. In both intact and stripped preparations the basal short-circuit current (SCC) was greater and the tissue resistance lower in the jejunum than in the ileum. 5-HT caused concentration-dependent increases in SCC in intact and stripped preparations of both regions. EC50 values were similar in the jejunum and ileum, stripped sheets from both regions showing greater sensitivity. In the ileum the maximum increase in SCC induced by 5-HT was similar in intact and stripped sheets, but in the jejunum the response was greater in intact preparations. The jejunal response to 5-HT was reduced in the absence of bicarbonate but unaffected by lack of chloride, whereas the ileal response was inhibited by removal of chloride but unaltered in bicarbonate-free conditions. In intact sheets the tetrodotoxin-sensitive neural component was greater in the jejunum. In stripped sheets a neural component could still be detected in the ileum, but not in the jejunum.

There are, therefore, fundamental differences in the way in which the jejunum and ileum respond to 5-HT stimulation—the jejunal response is primarily a result of stimulation of bicarbonate secretion whereas chloride secretion predominates in the ileum. The myenteric plexus appears to play a more prominent role in the jejunum; in the ileum other neural elements also contribute to the response.
Cirsimarin and Cirsimaritin, Flavonoids of Microtea debilis (Phytolaccaceae) with Adenosine Antagonistic Properties in Rats: Leads for New Therapeutics in Acute Renal Failure
Authors: Hasrat J A , De Bruyne T , De Backer J-P , Vauquelin G , Vlietinck A J
Published: April 2011

In traditional medicine Microtea debilis is used against proteinuria. In ligand-binding studies extracts of Microtea debilis have been shown to inhibit the binding of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) to adenosine-A1 receptors in rat forebrain membranes. Subsequently, cirsimarin, a flavonoid, was isolated as the active component and was shown to function as adenosine antagonist at the adenosine-A1 receptor in-vitro. In this study we have investigated the adenosine-A2 receptor activity of cirsimarin the in-vivo inhibition of the effects of adenosine by cirsimarin in rats, the absorption of cirsimarin and the inhibition of the binding of [3H]DPCPX to the adenosine-A1 receptor by urine samples obtained after oral administration of crude extract of Microtea debilis, cirsimarin or cirsimaritin to rats.

Cirsimarin inhibited the binding of [3H]5′-N-ethylcarboxamidoadenosine ([3H]NECA) to adenosine-A2 receptors in rat striatum with an inhibition constant, Ki, of 6.5 ± 0.3 μm. The decrease of heart rate and blood pressure induced by adenosine was significantly inhibited by cirsimarin. After oral administration of 8 and 80 mg kg−1 cirsimarin, the compound could not be detected in either plasma or urine, but the presence of cirsimaritin was established. By use of β-glucuronidase, glucuronides of cirsimaritin were also detected in the urine. The concentrations of cirsimaritin in the plasma were 0.126 ± 0.04, 0.138 ± 0.015, and 0.120 ± 0.022 μm, respectively, 2, 5 and 12 h after administration of 8 mg kg−1 cirsimarin. The concentrations of cirsimaritin in the urine at the same times after administration of the same dose were 205 ± 1.86, 5.05 ± 2.6 and 2.06 ± 0.09 μm, respectively. The inhibition of the binding of [3H]DPCPX to the adenosine-A1 receptor by urine samples collected 2, 5 and 12 h after oral administration of 8 mg kg−1 cirsimarin or a crude extract of Microtea debilis containing approximately 8 mg kg−1 cirsimarin and 2.8 mg kg−1 cirsimaritin, or 6.8 mg kg−1 cirsimaritin, was not significantly different from that of urine samples collected from untreated rats, in contrast with urine samples collected 1 and 2 days after oral administration of 80 mg kg−1 cirsimarin. Approximately 3% of the cirsimarin was excreted in the urine as cirsimaritin.

The results indicate that in the kidney and urinary tract the concentrations of cirsimaritin produced after ingestion of more than 8 mg kg−1 cirsimarin can be high enough to inhibit the interaction of adenosine with its receptors; this might explain the effectiveness of Microtea debilis preparations against proteinuria in traditional medicine.
Evaluation of the Long-term Effects of Oleum Origani on the Toxicity Induced by Administration of Streptozotocin in Rats
Authors: Lermioglu Ferzan , Bagci Seyfi , Onderoglu Selda , Ortac Ragip , Tugrul Levent
Published: April 2011

Oleum origani, the essential oil of Origanum onites L., is a traditional plant material used in Turkey for the treatment of several diseases, including diabetes mellitus. This study has evaluated the effect of oleum origani on streptozotocin-induced tissue injury and haematological changes. The effect of oleum origani on glycaemia was also studied.

Long-term administration of oleum origani resulted in significant improvement of tissue injury induced by streptozotocin treatment. No effect on blood glucose levels was detected. In addition, any visible toxicity or disturbance of haematological parameters and tissue structure attributable to the long-term use of oleum origani were not established in normal rats.

The data indicate that long-term use of oleum origani might be effective in preventing or at least in retarding the development of some complications of diabetes mellitus. Further investigation is required to determine the underlying mechanism(s) of the protective effect against tissue injury induced by streptozotocin-treatment of rats.
Oestradiol Release from Self-setting Apatitic Bone Cement Responsive to Plasma-calcium Level in Ovariectomized Rats, and its Physicochemical Mechanism
Authors: Otsuka Makoto , Yoneoka Kazuki , Matsuda Yoshihisa , Fox Jeffrey L , Higuchi William I , Sugiyama Yuichi
Published: April 2011

The effect of plasma calcium levels on the release of oestradiol from a self-setting apatite bone cement containing 0.5% oestradiol was investigated in ovariectomized rats.

The profiles of in-vitro release from the cements in simulated body fluid containing 0, 5 or 10 mg calcium per 100 mL indicated that the rate of release of oestradiol decreased with increasing calcium concentration in the dissolution media. After subcutaneous implantation of oestradiol-loaded cement in healthy and vitamin D-deficient rats, oestradiol release in diseased rats with low plasma calcium levels was significantly higher than that in healthy rats.

These results suggest that in-vitro release of oestradiol from apatite bone cement was dependent on the calcium concentration in the buffer and that the in-vivo release of oestradiol from apatite bone cement was dependent on plasma calcium levels.
Effects of Endotoxin on Neurally-mediated Gastric Acid Secretion in the Rat
Authors: Ramirez Carmen , Calatayud Sara , Beltrán Belen , Martínez-Cuesta Angeles , Barrachina Dolores
Published: April 2011

The effects of a peripheral administration of E. coli endotoxin on neurally-mediated gastric acid secretion and the role of endogenous opioids or PAF receptors in endotoxin effects have been evaluated in the continuously perfused stomach of the anaesthetized rat.

Gastric acid secretion stimulated by distension (20 cm H2O) was reduced dose-dependently by single intravenous bolus injection of endotoxin (0.1–10 μg kg−1). Doses of 5 μg kg−1 induced a peak reduction of distension-stimulated acid output and significantly reduced the secretory response induced by an intravenous bolus of 2-deoxy-d-glucose (150 mg kg−1). This dose of endotoxin did not significantly modify mean systemic arterial blood pressure throughout the experimental period. Pretreatment with the opioid receptor antagonist naloxone (1 mg kg−1, i.v.) or the platelet-activating factor (PAF) receptor antagonist WEB 2086 (2 mg kg−1, i.v.) did not reverse the inhibitory effects of endotoxin (5 μg kg−1, i.v.) on acid secretion stimulated by both distension and 2-deoxy-d-glucose.

These findings suggest that endotoxin-induced acute inhibition of neurally-mediated acid responses, stimulated by gastric distension or administration of 2-deoxy-d-glucose, do not involve the activation of endogenous opioids or PAF receptors.
Evaluation of Liver Function by Co-administration Methodology Using 13C-Labelled Benzoic Acid and Hippuric Acid Coupled with Nuclear Magnetic Resonance Spectroscopy
Authors: Akira Kazuki , Negishi Eiji , Yamamoto Chiaki , Baba Shigeo
Published: April 2011

The amount of hippuric acid synthesized and excreted in the urine after benzoic acid loading (hippuric acid test) is a useful index of liver function. However, the hippuric acid test gives erroneous results in the event of failure of renal excretory function. A new stable isotope co-administration methodology using nuclear magnetic resonance (NMR) spectroscopy has been developed to overcome this defect.

[7-13C]Benzoic acid and [glycine carbonyl-13C]hippuric acid ([gly-13C]hippuric acid), each 0.4–0.6 mmol kg−1 were simultaneously administered intravenously as probes to normal or liver-injured rats and the urine was analysed by 100 MHz 13C NMR spectroscopy. Consequently, urinary excretion of [7-13C]hippuric acid formed from [7-13C]benzoic acid and [gly-13C]hippuric acid was successfully traced with very simple and convenient procedures. The urinary excretion of [7-13C]hippuric acid indicated the combined functions of hippuric acid synthesis and renal excretion, whereas that of [gly-13C]hippuric acid was indicative of renal excretion of hippuric acid only. The heights of resonances for C7 of [7-13C]hippuric acid and the glycine carbonyl carbon of [gly-13C]hippuric acid were used to calculate the concentrations of labelled hippuric acids. [7-13C]Hippuric acid was excreted more slowly than [gly-13C]hippuric acid by both normal and liver-injured rats. The liver-injured rats excreted the labelled hippuric acids more slowly than the normal rats. The kinetic parameters were computed for the individual rats on the basis of Michaelis-Menten elimination for benzoic acid and first-order elimination for hippuric acid. The maximum rates of metabolism (Vmax) (4.8–5.8 μmol min−1 kg−1) and the renal elimination rate constants of hippuric acid (Kre) (0.010–0.021 min−1) in the liver-injured rats were lower than those (Vmax 6.7–11.8 μmol min−1 kg−1; Kre 0.026–0.045 min−1) in the normal rats.

These results have demonstrated that liver function can be evaluated from the Vmax value even though the renal function of hippuric acid excretion (Kre) is impaired. Thus the co-administration methodology is feasible and can remove the defect of the previous hippuric acid test. These results could form the basis for a more convenient and reliable hippuric acid test in man.
Predictions of Carbamazepine Concentrations Using a Bayesian Program (PKS System, Abbott): A Retrospective Evaluation in an Outpatient Population
Authors: Gaulier J M , Boulieu R , Fischer C , Mauguiere F
Published: April 2011

This work evaluates the performance of a Bayesian program (PKS System, Abbott) for predicting carbamazepine concentrations in an outpatient population. The retrospective study involved 20 epileptic patients (12 adults and 8 children) receiving carbamazepine monotherapy orally. The program was used to predict measured serum levels after feedback of 0, 1 or 2 steady-state concentrations.

A significant negative prediction bias was observed when no feedback concentration was used for estimation. However, the prediction bias (mean prediction error; m.e.) decreased as soon as one feedback concentration was used for estimation. Precision (mean absolute prediction error; m.a.e.) was significantly improved with one feedback concentration and was even better with two concentrations. Likewise, r.m.s.e. (root mean squared error; composite of bias and precision) regularly decreased when the number of feedback concentrations used was increased. Eleven percent of the estimates were unacceptable clinically (prediction error >2 mg L−) when 1 feedback concentration was used; less than 3% were unacceptable when two concentrations were used.

Thus the performance of the Bayesian dosing program is acceptable when two feedback concentrations are known, and seems able to help the clinician adjust carbamazepine dosage in an outpatient population.
Lecithinization of IL-6 Enhances Its Thrombopoietic Activity in Mice
Authors: Igarashi R , Tsutsumi Y , Fujii H , Tsunoda S , Ochiai A , Takenaga M , Morizawa Y , Mayumi T , Mizushima Y
Published: April 2011

This study was conducted to assess the merit of lecithinization of recombinant human interleukin-6 (IL-6) as a drug delivery system.

IL-6 was lecithinized by covalently binding it with a phosphatidylcholine (lecithin, PC) derivative. The in-vivo thrombopoietic potency of lecithinized IL-6 (PC-IL-6) was greater than that of native IL-6 when administered subcutaneously, although the in-vitro bioactivity of PC-IL-6 was markedly reduced by lecithinization. When PC-IL-6 and native IL-6 were given in doses that produced the same level of thrombopoietic activity, the former stimulated less production of IgG1, a marker of the adverse effects of IL-6, than did the latter. Furthermore, PC-IL-6 persisted in the blood longer than native IL-6.

Based on the above, PC-IL-6 appears to be useful as a drug delivery system and may also be useful in the treatment of drug-induced thrombocytopenia.
Synthesis and Biological Evaluation of New 3-Aralkylamino-2-aryl-2H-1,2,4-pyridothiadiazine 1,1-dioxides as Potential CCK-Receptor Ligands
Authors: de Tullio Pascal , Pirotte Bernard , Neven Philippe , Masereel Bernard , Dewalque Daniel , Diouf Ousmane , Podona Tchao , Caignard Daniel , Renard Pierre , Delarge Jacques
Published: April 2011

A series of 2-aralkyl-4H-pyridothiadiazine 1,1-dioxides and 3-aralkylamino-2-aryl-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to quinazolinone CCK receptor antagonists were synthesized and evaluated as CCK-A and CCK-B receptor ligands.

The compounds were effective as cholecystokinin-ligands in the micromolar range of concentration, c.f. the cholecystokinin receptor antagonists asperlicin, lorglumide or benzotript, and were thus less potent than the best quinazolinones previously reported.

Although the compounds were unsuitable for drug use, the work contributed to our understanding of the chemistry of unusual 2,3-disubstituted pyridothiadiazinedioxides.
Investigation of Physicochemical Changes to l-Asparaginase During Freeze-thaw Cycling
Authors: Jameel Feroz , Bogner Robin , Mauri Frank , Kalonia Devendra
Published: April 2011

l-Asparaginase derived from Erwinia chrysanthemi which is being investigated as an alternative to E. coli for the treatment of lymphoblastic leukaemia has been found in our laboratory to lose activity upon exposure to consecutive freeze-thaw cycles. An investigation was undertaken using several techniques to characterize fully the physicochemical changes l-Asparaginase is undergoing during freeze–thaw cycling leading to the loss of its activity.

A total protein assay suggested that the loss of some enzyme activity was a result of protein precipitation. Circular dichroism (CD) studies showed a decrease of α-helical structure with a concomitant increase in β sheet and random coil content, suggesting alterations in the secondary structure leading to unfolding, the first step of denaturation processes. The elution profiles obtained from size-exclusion chromatography (SEC) studies indicated the formation of several species during the process of freezing and thawing. Sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE) studies showed bands corresponding to 1–3 kDa and 32 kDa, suggesting that some of the species are fragments and shortened monomers resulting from cleavage of monomers. The molecular weight distribution obtained using SEC-linked light scattering indicated a substantial fraction of polydispersed fragments ranging from 900 Da to 3 kDa and a small fraction of aggregates corresponding to 300 kDa.

A scheme was proposed to explain the cascade of events leading to the loss of soluble protein and accompanying loss of enzyme activity. Tetramers of the enzyme dissociate into monomers some of which are cleaved into small fragments. The shortened monomers then aggregate and precipitate.
A Structure-Relationship Study of the Uptake of Aliphatic Polyamine Compounds by Rat Intestinal Brush-border Membrane Vesicles
Authors: Kobayashi Michiya , Suruga Sachie , Takeuchi Hirotaka , Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi
Published: April 2011

The effects of lipophilicity, ion-diffusion potential and membrane surface potential on the uptake of various aliphatic polyamine compounds by rat intestinal brush-border membrane vesicles (BBMV) have been investigated.

A valinomycin-induced potassium-diffusion potential (inside-negative) stimulated the initial uptake of diamine compounds, and good correlation was observed between lipophilicity and the amount of diffusion-potential-dependent transport of the diamines. In contrast, because of their much lower lipophilicity, tri- and tetraamine compounds were not affected by the diffusion potential. Tetracaine, which can make the membrane surface potential more positive, inhibited the transport rate of 1,9-nonanediamine, spermidine and spermine by the BBMV.

These data suggest that the transport mechanism of diamines is similar to that of monoamine compounds in respect to its dependence on ion-diffusion potential and on the membrane surface potential. The extent of the effect of ion-diffusion potential on the rate of transport of the diamines was closely related to the lipophilicity of the diamine. In contrast, only the surface potential contributed to the transport mechanism of lower lipophilic tri- and tetraamine compounds.
Inhibitory Effects of N-acetylcysteine on Superoxide Anion Generation in Human Polymorphonuclear Leukocytes
Authors: Villagrasa Victoria , Cortijo Julio , Martí-Cabrera Miguel , Ortiz José L , Berto Luisa , Esteras Antonio , Bruseghini Leo , Morcillo Esteban J
Published: April 2011

It has been suggested that reactive oxygen species released by activated polymorphonuclear leukocytes (PMN) in man is one mechanism of tissue injury. Therapeutic action aimed at increasing antioxidant defence mechanisms is still a clinical challenge. This study examines the activity of N-acetylcysteine, a known antioxidant, in the protection of PMN exposed in-vitro to the chemoattractant peptide fMet-Leu-Phe (FMLP), the protein kinase C activator phorbol myristate acetate or the lipid peroxidation promoter t-butyl hydroperoxide.

FMLP (3–300 nm) and phorbol myristate acetate (160 pm–160 nm) induced concentration-related superoxide anion generation. Pre-treatment with N-acetylcysteine (33–333 μm) resulted in concentration-related inhibition of superoxide production induced by FMLP (30 nm) or phorbol myristate acetate (16 nm); –log IC50 values were 3.97 ± 0.07 and 3–91 ± 0.10, respectively. Changes in intracellular calcium ion concentration ([Ca2+]i) induced by FMLP (30 nm) were studied in fura-2-loaded human PMN. FMLP produced a transient calcium response, i.e. a peak followed by decay to a residual value above baseline. N-Acetylcysteine (333 μm) did not affect either basal [Ca2+]i values or changes in [Ca2+]i values after treatment with FMLP. Activation by phorbol myristate acetate caused a reduction in glutathione levels from 5.94 ± 0.86 (control) to 1.84 ± 0.51 nmol/3 × 106 cells (P < 0.05 compared with control). Pre-treatment with N-acetylcysteine (333 μm) fully reversed the reduction in glutathione levels induced by phorbol myristate acetate (4.83 ± 0.68 nmol/3 × 106 cells; P > 0.05 compared with control). Exposure to t-butyl hydroperoxide (0.5 mm, 30 min) markedly increased malondialdehyde levels (from 0.03 ± 0.02 to 0.73 ± 0.07 nmol/106 cells), and index of lipid peroxidation. Malondialdehyde levels were significantly reduced in PMN treated with N-acetylcysteine (333 μm; 0.55 ± 0.04 nmol/106 cells; P < 0.05 compared with untreated cells exposed to t-butyl hydroperoxide).

In conclusion, N-acetylcysteine reduces superoxide generation in response to FMLP and phorbol myristate acetate and partially protects against lipid peroxidation in PMN from man. The protection afforded by N-acetylcysteine is not related to alteration of the intracellular calcium signal but might be effected by replenishment of the intracellular glutathione levels.
2′,5′-Dihydroxychalcone as a Potent Chemical Mediator and Cyclooxygenase Inhibitor
Authors: Lin Chun-Nan , Lee Tai-Hua , Hsu Mei-Feng , Wang Jih-Pyang , Ko Feng-Nien , Teng Che-Ming
Published: April 2011

Eleven chalcone derivatives have been tested for their inhibitory effects on platelet aggregation in rabbit platelet suspension and the activation of mast cells and neutrophils.

Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the compounds and some also had a potent inhibitory effect on collagen-induced platelet aggregation and cyclooxygenase. Some hydroxychalcone derivatives showed strong inhibitory effects on the release of β-glucuronidase and lysozyme, and on superoxide formation by rat neutrophils stimulated with the peptide fMet-Leu-Phe (fMLP). We found that the anti-inflammatory effect of 2′,5′-dihydroxychalcone was greater than that of trifluoperazine. 2′,5′-Dihydroxy and 2′,3,4,4′-tetrahydroxyl chalcones, even at low concentration (50 μm), tested in platelet-rich plasma from man almost completely inhibited secondary aggregation induced by adrenaline.

These results suggest that the anti-platelet effects of the chalcones are mainly a result of inhibition of thromboxane formation.
A Sulphonoglycolipid from the Fern Polypodium decumanum and its Effect on the Platelet Activating-factor Receptor in Human Neutrophils
Authors: Vasänge Mervi , ROLFSEN Wenche , Bohlin Lars
Published: April 2011

The South American fern Polypodium decumanum, traditional name calaguala, has documented clinical use in oral treatment of skin disorders, including psoriasis. The inflammatory mediator platelet-activating factor (PAF), has been implicated in the pathogenesis of psoriasis.

A constituent of a calaguala extract has been shown to have inhibitory activity in a PAF-induced exocytosis model in human neutrophils. The compound was identified as the sulphoquinovosyl diacylglycerol 1,2-di-O-palmitoyl-3-O-(6-sulpho-α-d-quinovopyranosyl)-glycerol by spectroscopic means. When subsequently studied in an in-vitro model for [3H]PAF binding in neutrophils from man the compound caused dose-dependent displacement of [3H]PAF from its receptor with an IC50 value of 2 μm. It is suggested that the compound acts through PAF receptor antagonism in intact human neutrophils.
An Interfacial Tension Model of the Interaction of Water-soluble Polymers with Phospholipid Composite Monolayers
Authors: Anderson Keith E , Rogers James A , Li Dongqing
Published: April 2011

The axi-symmetric drop-shape analysis-pendant drop technique has been used to measure interfacial tension at the chlorobenzene–water interface in the presence of adsorbed films of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), DMPC–cholesterol, DPPC–cholesterol, DMPC–cholesterol–dicetyl phosphate (DCP) and DPPC–cholesterol–DCP.

A surface-pressure function, n* = πlipid–polymer - πlipid (where πlipid is the surface pressure of the mono-layer without polymer and πliPid-poiymer is the surface pressure of the lipid mono-layer and adsorbed polymer at equilibrium at the chlorobenzene-water interface) was used to characterize the interaction of eight water-soluble polymers with the lipid films. The equation, Δπ* = πII* - πI* (where the subscripts II and I denote the higher and lower lipid composites, respectively) was used to determine the differential effect of cholesterol and DCP on mono-layer characteristics in the presence of 1% w/v polymer. Cholesterol or polymer individually condensed DMPC films and expanded DPPC films. However, composite films of DMPC–cholesterol–DCP and carboxymethylchitin (CM-chitin), poly(acrylic acid) (PAA) or poly(vinyl alcohol) (PVA) were more expanded than DMPC films whereas composite films of DPPC were neither more condensed nor expanded than DPPC films. A polymer impact ratio, P* = πlipid-poiymer/πlpolymer was calculated and the polymers were ranked in order of their impact on the lipid film. PVA and polysaccharides gave low and high P* values, respectively, corresponding to high and low levels of film interaction, whereas PAA and hydrophobized polysaccharides gave intermediate values, indicating their affinity for and penetration of interfacial films with little disruption of the mono-layer.

The results show that measurement of interfacial pressures at the chlorobenzene–water interface might be advantageous for evaluating the action of polymers on biological membranes.
The Effect of Monomers and of Micellar and Vesicular Forms of Non-ionic Surfactants (Solulan C24 and Solulan 16) on Caco-2 Cell Monolayers
Authors: Dimitrijevic Dejana , Lamandin Charlotte , Uchegbu Ijeoma F , Shaw Andrew J , Florence Alexander T
Published: April 2011

Measurements of transepithelial electrical resistance (TEER), the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) test and monitoring of poly(ethylene glycol) (PEG) transport have been used to study the effects of the non-ionic surfactants Solulan C24 and Solulan 16, either free in solution or as an integral part of niosome bi-layers, on intestinal epithelial cells from man (Caco-2 cell monolayers).

The effects on epithelial integrity and on the transport of the hydrophilic drug metformin depend on the concentration of the surfactants. At concentrations above 1% the effect on TEER of the surfactant in niosomal form and free in solution were equivalent whereas cell viability was preserved to a higher concentration of Solulans when the Solulans were present in the niosomal form.

It was concluded that the toxic effect of niosomes arises from free surfactant present in the niosome suspension.