bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-activity Relationships of Some Novel Coronary Dilator Derivatives of Palmitoyl Carnitine in the Rat Isolated Heart
Authors: Reeves K A , Dewar G H , Rad-Niknam M , Woodward B 
Published: April 2011

Abstract
The structure-activity relationships of some novel coronary dilator derivatives of palmitoyl carnitine in the rat isolated perfused heart are described.
It has been shown previously that esterification of palmitoyl carnitine changes the activity of the compound from a coronary constrictor to a coronary dilator. In this study, it was found that the ester group is not a necessary requirement for coronary dilator activity, but only the absence of the negatively charged carboxylic acid group of palmitoyl carnitine, as compounds containing an ethyl group in place of the ester group were also active coronary dilators. Furthermore, substituting the methyl groups attached to the nitrogen atom of the molecule profoundly altered coronary dilator activity. A quaternary ammonium group was a necessary requirement for potent coronary dilator activity.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 15&#x006d;̇7 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

Abstract
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

Abstract
In the female mouse, dapsone (50–500 mg kg−1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0&#x006d;̇5-1 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.