bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the disulphide bonds in endothelin-1
Authors: Pelton John T , Miller Robert C
Published: April 2011

The smooth muscle contracting peptide endothelin-1 is characterized by the presence of two disulphide bonds and their importance for maintaining the agonist activity of the peptide was examined by synthesizing analogues of endothelin-1 lacking one or the other, or both, of these bonds. The circular dichroic spectra of these analogues (in which alanine residues replaced the appropriate cystines), [Ala1,15]-, [Ala3,11]- and [Ala1,3,11,15]-endothelin-l had features in common with that of endothelin-1. All three analogues exhibited at least some agonist activity in guinea-pig isolated trachea, but surprisingly endothelin-1 was a partial agonist in comparison with the analogue [Ala3,11]endothelin-1. The disulphide bonds are therefore not absolutely essential for maintaining the tertiary structure necessary for agonist activity at endothelin-1 receptors in all tissues.
Peripheral benzodiazepines potentiate the effect of adenosine in rat vas deferens
Authors: Escubedo Elena , Camarasa Jorge , Pallas Mercé , Adzet Tomás
Published: April 2011

Ro 5–4864, diazepam, clonazepam and PK 11195 inhibit the responses of rat vas deferens following electrical stimulation in the rank order Ro 5–4864 > PK 11195 = diazepam > clonazepam. The adenosine-inhibited electrically-induced response was potentiated by Ro 5–4864 or diazepam, but not by clonazepam or PK 11195. This potentiation is due to an inhibition of the adenosine uptake system.
Corticosterone and prolactin response to TFMPP in rats during repeated antidepressant administration
Authors: Poland Russell E , Frazer Alan
Published: April 2011

The corticosterone and prolactin response to acute administration of the 5-HT agonist 1-(m-trifluoromethylphenyl) piperazine (TFMPP) (10 mg kg−1) was assessed in rats treated for 10 days with either saline, amitriptyline (20 mg kg−1 day−1) or nialamide (40 mg kg−1 day−1). For all groups, TFMPP significantly increased both serum corticosterone and prolactin concentrations compared with control animals challenged with saline. However, the corticosterone response to TFMPP was attenuated significantly by nialamide pretreatment, while the prolactin response to TFMPP was enhanced significantly by amitriptyline pretreatment. These results support previous reports that antidepressants differentially affect 5-HT-ergic systems involved in the regulation of corticosterone and prolactin secretion.
Enhancement of Amrinone-induced Positive Inotropy in Rabbit Papillary Muscles with Depressed Contractile Function: Effects on Cyclic Nucleotide Levels and Phosphodiesterase Isoenzymes
Authors: Shahid M , Rodger I W
Published: April 2011

The inotropic activity of amrinone and its effects on cyclic nucleotide levels in rabbit papillary muscles with normal and depressed contractile function have been compared. The effects of amrinone on the cyclic (c) AMP hydrolytic activity of cyclic nucleotide phosphodiesterase (PDE) isoenzymes were also examined. Amrinone (2.4 × 10−4-1.2 × 10−3 M) produced a relatively weak (maximal increase 11%) positive inotropic effect in papillary muscles stimulated at the near optimal stimulation frequency of 1 Hz. In contrast, large positive inotropic responses (maximal 138–200%) were obtained with amrinone in papillary muscles in which contractile force had been depressed by: (a) lowering stimulation frequency to 0.4 Hz, (b) reducing extracellular Ca2+ concentration from 2.5 × 10−3 M to 6.3 × 10−4 M, (c) prior addition of sodium pentobarbitone (6.5 × 10−4 M). The EC50 values for amrinone under conditions (a), (b), and (c) were 3.0 × 10−3, 2.6 × 10−3, and 2.8 × 10−3 M, respectively. Force-frequency curves in rabbit papillary muscles were compared at normal (2.5 ×10−3 M) and low (6.3 × 10−4 M) extracellular Ca2+ concentration. Contractions at low frequencies of stimulation (< 0.4 Hz) were less sensitive to removal of extracellular Ca2+ than higher stimulation rates indicating that in the former situation, recycling of intracellular Ca2+ is more important for maintaining contractile force. The positive inotropic effects of amrinone in normal and papillary muscles with depressed contractile force were associated with similar increases in both cAMP (1.6-2.5 fold) and cGMP (2.6-4.0 fold) levels, despite marked differences in the degree of inotropy in these muscles. The cGMP inhibited cAMP-PDE (PDE III) was selectively inhibited by amrinone (IC50 9.9 × 10−5 M), whilst the activities of Ca2+/calmodulin-stirnulated PDE, cGMP-stimulated PDE and cGMP-insensitive PDE were only weakly affected (IC50 > 2.5 × 10−4 M). The results show an involvement of cAMP in the mechanism underlying the positive inotropic action of amrinone in cardiac muscle with depressed contractile force. Furthermore, it is suggested that there may be an enhanced effectiveness of cAMP on intracellular Ca2+ mobilization in depressed cardiac muscle.
Effect of Some Cationic Amphiphilic Drugs on Phospholipid Methylation in the Central Nervous System of Rats
Authors: Nocon Halina , Melzacka Miroslawa
Published: April 2011

Imipramine, desipramine, citalopram and chlorpromazine in concentrations which corresponded with their concentration in the central nervous system of rats after pharmacological doses, potentiated phospholipid methylation in the synaptic cortical membranes of naive rats in-vitro. Chronic administration of imipramine, desipramine or citalopram induced changes in the activity of phospholipid methyltransferases since none of these drugs stimulated phospholipid methylation in the synaptic cortical membranes of rats treated with these antidepressants for two weeks. In contrast, chronic treatment with chlorpromazine did not change the sensitivity of phospholipid methyltransferases to the stimulating effect of chlorpromazine, whereas addition of haloperidol to the synaptic cortical membranes of rats treated chronically with haloperidol led to a decrease of phospholipid methylation.
Reconsideration of inhibitory effect of metformin on intestinal glucose absorption
Authors: Wilcock Carol , Bailey Clifford J
Published: April 2011

New evidence that metformin increases intestinal glucose metabolism has necessitated a re-examination of the effect of metformin on intestinal glucose absorption. Normal 18 h fasted mice received an intragastric bolus of metformin 2 h before preparation of everted gut sacs from the proximal, middle and distal regions of the jejunum and ileum. Net mucosal glucose transfer from the intestinal lumen into the tissue was reduced by 15 and 28% after 50 and 250 mg kg−1 metformin, respectively (ANOVA, P < 0.05). Net glucose transfer into the serosal fluid was reduced by 12 and 70% after 50 and 250 mg kg−1 metformin respectively (ANOVA, P < 0.05 and P < 0.01). The inhibitory effect of metformin on both the mucosal and serosal glucose transfer mechanisms was greatest in the middle portion of the small intestine. The results suggest that metformin decreases intestinal glucose absorption in a dose-dependent manner by effects on mucosal and serosal glucose transfer.
Electrochemical determination of the permeability of porcine mucus to model solute compounds
Authors: Desai M A , Nicholas C V , Vadgama P
Published: April 2011

An electrochemical approach to the determination of permeability through native mucus gel of simple electrochemically active solutes is reported. For all the the solutes studied, a reduction in effective diffusion coefficients was observed, with retardation of solute flux by a factor of at least two. However, NADH and the dicarboxylic acid derivative of ferrocene demonstrated a substantial, almost ten-fold, reduction in permeability through mucus. Results for the controls were in reasonable agreement with literature values where available. No consistent effect of molecular weight was evident with regard to the barrier properties of mucus over the molecular weight range of solutes investigated (34–660 daltons). The results suggest that mucus is acting more than as a gel support for an unstirred water layer.
Concentration of ibuprofen in cervical mucus
Authors: Salas-Herrera I G , Pearson R M , Turner P
Published: April 2011

Concentrations of an acidic drug, ibuprofen, in cervical mucus and serum have been measured by HPLC after oral administration in six healthy volunteers. After an 800 mg single dose of ibuprofen, the concentration reached in cervical mucus was less than 4% of that in serum. It is postulated that because ibuprofen is an acidic drug which is not subject to ‘ion-trapping’ in the acidic environment of cervical mucus, it is not concentrated in this secretion.
Analogues of Triprolidine: Structural Influences upon Antihistamine Activity
Authors: Casy A F , Ganellin C R , Mercer A D , Upton C
Published: April 2011

The synthesis of some geometrical isomers related to triprolidine is reported. Previous configurational assignments, by UV and proton NMR, are validated by high field nuclear Overhauser enhancement methods and the isomeric purity of tested E- and Z-isomers was greater than 99.5% as assessed by an HPLC method developed for these compounds. Affinity constants for triprolidine (E and Z) in guinea-pig ileum showed a potency ratio of ∼600 whereas at cerebellar sites this ratio was only ∼100, suggesting that the H1 receptor in these two tissues may not be identical. In-vivo tests using a lethal dose of compound 48/80 (a potent histamine-releasing agent) demonstrated that triprolidine itself was the most active compound to protect the animal among all the isomeric compounds tested: in all isomeric pairs the E-configuration possessed superior activity over Z. The disposition of the aryl groups in these geometrically constrained compounds mimics that seen in the structurally related chiral pheniramines which are sp3 hybridized and whose absolute stereochemistry is known.
Binding Potency of Paroxetine Analogues for the 5-Hydroxytryptamine Uptake Complex
Authors: Mathis Chester A , Gerdes John M , Enas Joel D , Whitney John M , Taylor Scott E , Zhang YI , Mckenna Dennis J , Havlik Sona , Peroutka Stephen J
Published: April 2011

The in-vitro inhibition constants (Ki) of 14 structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor paroxetine were determined to assess the structure-affinity relationship of these derivatives. A goal of these studies was to determine those positions on paroxetine which could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as [18F]fluoroalkyl groups might be appended for future in-vivo imaging studies of the 5-HT uptake system. Using the methyl moiety as a steric probe for these studies, it was found that the rank order of potency of various methyl-substituted paroxetine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT re-uptake site was: 4′≅ 3′-≅ 2″->2′-≅ 1- >5″-> 6″-methyl. The in-vitro equipotent molar ratios (EPMR, Ki(analogue)/Ki(paroxetine)) of the analogues were determined, and the EPMRs of the 4′-,3′-, and 2″-methyl derivatives were 1·9, 2·2 and 2·2, respectively. The 4′- and 2″-fluoromethyl and -fluoroethyl analogues were synthesized, and the EPMRs of the 4′- and 2″-fluoromethyl derivatives were determined to be 2·0 and 3·5, and those of the 4′- and 2″- fluoroethyl analogues were 5·2 and 6·2, respectively. The 2″-fluoromethyl analogue was unstable in aqueous solutions, and it is not a promising ligand for in-vivo studies. The 4′-fluoromethyl derivative was stable in aqueous solutions and, based upon its relatively high affinity, is a candidate for radiolabelling with 18F for in-vivo positron emission tomography studies of the 5-HT re-uptake site.
In-Vivo Pharmacological Studies of 2-N-Carboxamidinonormianserin, a Histamine and 5-Hydroxytryptamine Antagonist Lacking Central Effects
Authors: Leitch I M , Boura A L A , Edwards P , King R G , Rawlow A , Rechtman M P
Published: April 2011

The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1, 2, 3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-α)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30–100 μg kg−1, i.v.) caused long-lasting (>1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (≤lmg kg−1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11α,9α-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0·3–1·0 mg kg−1, i.v.). Higher doses of FCC5 (3 mg kg−1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0·1–1·0 mg kg−1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0·1–0·3 mg kg−1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0·76 mg kg−1, i.p.; and 2·7 mg kg−1, p.o.). In decerebrate rats which had been spinalized at T6–8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0·36 mg kg−1, i.p.) but not by FCC5 (≤3mg kg−1, i.p.). Head twitches in carbidopapretreated mice induced by l-5-hydroxytryptophan were inhibited by mianserin (ID50 0·11 mg kg−1, i.p.), but not by FCC5 (≤30 mg kg−1, i.p.). It is concluded that FCC5 possesses antihistamine and anti-5-HT properties and is orally effective. No evidence was found for central effects.
The Calcium Channel Blocker LAS 30538, Unlike Nifedipine, Verapamil, Diltiazem or Flunarizine, Potently Inhibits Insulin Secretion In-vivo in Rats and Dogs
Authors: Gristwood R W , Furman B L , Llenas J , Jauregui J , Berga P
Published: April 2011

The effects of a novel calcium channel blocker, LAS 30538 (1-[2-(2,6-dimethylphenoxy)ethyl]-α,α-bis-(p-fluorophenyl)-4-piperidine methanol), were studied on glucose tolerance and insulin secretion in rats and dogs in-vitro and in-vivo. Some comparisons were made with nifedipine, verapamil, diltiazem, flunarizine, diazoxide, cromakalim and minoxidil. LAS 30538, like a number of calcium channel blockers, was found to inhibit insulin secretion in-vitro, but was 1000-fold more potent than verapamil or diltiazem in this respect. LAS 30538 differed from the other calcium channel blockers studied in that it also potently inhibited insulin secretion and impaired glucose tolerance in-vivo. The evidence that LAS 30538 is more potent than diazoxide as a hyperglycaemic agent in-vivo suggests that this could be a useful drug for the treatment of hyperinsulinaemia in man.
Effects of cupric chloride and tamrabhasma, a traditional Indian preparation of copper, on eicosanoid production by human gastric and colonic mucosa
Authors: Goel R K , Tavares I A , Bennett A
Published: April 2011

Tamrabhasma is a traditional copper oxide-containing Indian preparation which has anti-ulcer activity. We have studied the effect of tamrabhasma and CuCl2· 2H2O on prostaglandin formation by human gastric and colonic mucosa and submucosa, as prostaglandins have mucosal protective activity, and their release may contribute to the anti-ulcer effect. With the gastric mucosa, tamrabhasma 10 μg mL−1, but not 01 or 1 μg mL−1, increased prostaglandin E (PGE) concentration by 38% (P < 0·005), with little or no effect on 6-keto-PGF1α, thromboxane B2 or the leukotriene (LT) LTC4/LTD4. CuCl2-2H2O (10 μg mL−1) increased 6-keto-PGF,α by 46% (P < 0·05), but 0·1, 1, 50 and 250 μg mL−1 did not significantly affect any of the prostanoids, and only the highest concentration reduced the amount of LTC4/LTD4. In the colon mucosa, tamrabhasma (0·1–10 μg mL−1) or CuCl2 · 2H2O (10–50 μg mL−1) increased all the prostanoids and this effect was greater than in the gastric mucosa but there was no significant change in LTC4/LTD4. CuCl2-2H2O showed a bell-shaped concentration-effect curve, with no significant effect at lower and higher amounts. Indomethacin (0·1–10 μg mL−1) caused a concentration-dependent reduction in the prostanoid amounts. The effect of tamrabhasma was probably not only due to the presence of Cu2+, as tamrabhasma was more effective than CuCl2-2H2O alone; in addition the solubility of CuO is very low. Increased prostanoid levels might explain, at least partly, the gastric mucosal protection by tamrabhasma. The results in the colon, however, raise the possibility that tamrabhasma should be examined for the treatment of inflammatory bowel disease.
Calcium Antagonism by Cobalt Ions on Contraction of Guinea-pig Taenia Coli
Authors: Nasu Tetsuyuki
Published: April 2011

In guinea-pig taenia coli, cobalt ions (Co2+) inhibited the tonic response to a highly concentrated K+ solution (high-K+, 40 Mm) more strongly than the phasic response. Co2+ displaced Ca2+ concentration-response curves to the right, inhibited the increase in tissue calcium content caused by high-K +, and inhibited Ca2+ binding at low affinity sites more than at high affinity sites. After treatment with Co2+, the tonic tension caused by high-K+ was not restored by a wash with normal medium, but it was restored by a wash with EDTA. The cobalt remaining in muscles was almost completely eliminated after a 20–30 min wash with EDTA. The results suggest that Co2+ binds chiefly to the surface membrane of taenia coli. Co2+ probably reduced the tension in response to high-K+ mainly by inhibiting Ca2+ influx rather than by affecting Ca2+ release.
Ultrastructural Alterations and DNA Synthesis of Renal Cell Nuclei following Cisplatin or Carboplatin Injection in Rats
Authors: Yasumasu Tetsuo , Ueda Toyofumi , Uozumi Jiro , Mihara Yukitaka , Koikawa Yasuhiro , Kumazawa Joichi
Published: April 2011

To clarify the difference in nephrotoxicity between cisplatin and carboplatin, ultrastructural alterations and DNA synthesis of renal cell nuclei were studied in Sprague-Dawley rats which had received intravenously either cisplatin or carboplatin at an equitoxic dose. Twelve hours after cisplatin injection, nucleolar segregation accompanied by aggregated nuclear heterochromatin was observed in the third segment of the proximal tubules. Seventy-two hours after cisplatin injection, nuclear damage was more widespread while regenerative cells were also observed. Nuclear damage was not observed in the carboplatin-treated rats. Nuclear DNA synthesis of renal cells was suppressed at 8, 12 and 24 h and was accelerated at 72 h after cisplatin injection. Carboplatin did not suppress nuclear DNA synthesis at any time. The results indicate that cisplatin, but not carboplatin, can affect the renal cell nuclei. Cisplatin-induced nephrotoxicity is related to its effects on renal cell nuclei.
Effect of Uraemia and Anephric State on the Pharmacokinetics of Tenoxicam in the Rat
Authors: Lopez-Bustamante L G , Troconiz J I F , Fos D
Published: April 2011

Renal alterations, uraemia and nephrotic syndrome induced in experimental animals caused a reduction in the plasma albumin concentration of 25 and 30%, respectively. As a result of this decrease, the unbound fraction of tenoxicam in uraemic rats (0·06 ± 0·02) and in anephric rats (0·11 ± 0·08) increased with respect to the control group (0·03±0·004). The induced hypoalbuminaemia did not modify the blood to plasma concentration ratio. Both plasma clearance (CL) and apparent volume of distribution at steady-state (Vdss) rose significantly with the increase in the unbound fraction: (Vdss 55 ±6 mL (control rats); 69 ± 12 mL (uraemic rats); 96 ± 30 mL (anephric rats); CL = 7± 1 mL h−1 (control rats); 12 ± 4 mL h−1 (uraemic rats); 15 ± 7 mL h−1 (anephric rats)). Tenoxicam elimination was found to be restrictive, with an extraction ratio less than 0·1 in the three groups. The induction of nephrotic syndrome was observed to have a significant effect on intrinsic metabolic activity, intrinsic clearance of tenoxicam being reduced by 30% in the anephric rats (161 ± 38 mL h−1) with respect to the values obtained in the control group (228 ± 22 mL h−1).
Pharmacokinetic Study of Gadolinium-DOTA in Control and Streptozocin Diabetic Rats
Authors: Michel A , Bonnet P A , Fernandez J P , Chambon C , Doucet D
Published: April 2011

The pharmacokinetics of gadolinium tetraazacyclododecanetetraacetic acid (Gd-DOTA), a contrast agent used in magnetic resonance imaging, have been evaluated in control and streptozocin-diabetic rats of different ages. In control rats, an age-related decrease in the Gd-DOTA elimination rate was noted, supported by a significantly lower apparent total body clearance and a significantly higher mean residence time. In diabetic rats, a similar but less important age-related change in the mean residence time and the apparent total body clearance was observed. Regardless of age-related differences in the pharmacokinetic parameters, a diabetic state induced several alterations in the Gd-DOTA pharmacokinetic parameters. The apparent total body clearance was significantly higher and the mean residence time significantly lower in diabetic rats indicating a higher elimination rate of Gd-DOTA. An important age-related increase in the volume of distribution at steady-state was noted in diabetic rats.
Binding of [3H]Haloperidol to Dopamine D2 Receptors in the Rat Striatum
Authors: Tsuchihashi Hiroshi , Sasaki Toko , Kojima Shigeko , Nagatomo Takafumi
Published: April 2011

The present study was designed to examine the properties of [3H]haloperidol binding to dopamine D2-receptors in rat striatum membranes, displacement potencies of various chemicals and differences between the affinities of various chemicals and two new 5-hydroxytryptamine (5-HT2) receptor antagonists, MCI-9042, (±)-2-(dimethylamino)-1-[[o-(m-methoxyphenetyl)phenoxy]methyl]ethyl hydrogen succinate hydrochloride and one of its metabolites. The plots of specific binding for the striatum membranes obtained from the Scatchard analysis using [3H]haloperidol were monophasic when nonspecific binding was determined with 10 μm chlorpromazine, and the Kd and Bmax values were 7·42±1·03 Nm and 1·58±0·20 pmol (mg protein)−1 (n= 10), respectively. The displacement potencies of D2 receptor, 5- HT2 receptor, histamine H1-receptor, and adrenoceptor antagonists were characterized by [3H]haloperidol binding to D2 receptors. The pKi values of a new antiplatelet agent, MCI-9042, and its metabolite were 5·02 and 5·53, respectively, and these values were lower than those of the D2-receptor antagonists, fluphenazine, spiperone, haloperidol, prochlorperazine, chlorpromazine, thioridazine, and sulpiride. They were also lower than the pKi values of the 5-HT2-receptor antagonists, pirenperone, ketanserin, methysergide, and mianserin. We conclude that the binding site of [3H]haloperidol in the rat striatum is the D2 receptor, that MCI-9042 and its metabolite have lower affinities for D2 receptors than for 5-HT2 receptors, and that this radioreceptor assay is useful for assessing the affinities of various agents.
The Ginkgo biloba extract, EGb761, increases synaptosomal uptake of 5-hydroxytryptamine: in-vitro and ex-vivo studies
Authors: Ramassamy C , Christen Y , Clostre F , Costentin J
Published: April 2011

The Ginkgo biloba extract (EGb 761) added to a synaptosomal fraction prepared from mice cerebral cortex modified [3H]5-hydroxytryptamine ([3H]5-HT) uptake in a biphasic manner. Between 4 and 16 μg mL−1 EGb 761 increased significantly the [3H]-5-HT uptake (maximum + 23%). A similar increase was also obtained when synaptosomes were prepared from the cortex of mice treated orally with EGb 761, either acutely (100 mg kg−1, 14 h and 2 h before death) or semi-chronically (2× 100 mg−1 kg daily for 4 consecutive days). The in-vitro increase in [3H]5-HT uptake induced by EGb 761 was not observed in the presence of 10−6  m clomipramine, a 5-HT-uptake inhibitor. EGb 761 did not increase [3H]dopa-mine uptake by synaptosomes prepared from striatum of mice. We investigated different fractions of EGb 761 in order to determine the compounds inducing the increase in [3H]5-HT uptake. The BN 52063 extract (corresponding to the EGb 761 devoid of flavonoid substances) did not increase [3H]5-HT uptake. The Cp 202 extract (corresponding to the EGb 761 devoid of terpenic substances and containing mostly flavonoid substances) increased [3H]5-HT uptake. Among the flavonoids, quercetin has been tested and had no effect on the [3H]5-HT uptake. Since at the usual therapeutic doses of EGb 761, the effective concentrations of the components responsible for this increase are likely to be reached in the brain, one may suggest that this effect could contribute to the therapeutic effect of EGb 761.
Cross-linked Chitosan Microspheres: Preparation and Evaluation as a Matrix for the Controlled Release of Pharmaceuticals
Authors: Thanoo B Chithambara , Sunny M C , Jayakrishnan A
Published: April 2011

Chitosan microspheres having good spherical geometry and a smooth surface were prepared by the glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in paraffin oil using dioctyl sulphosuccinate as the stabilizing agent. Microspheres having different degrees of swelling were made by varying the cross-linking density. Microspheres were prepared by incorporating theophylline, aspirin or griseofulvin. Drug incorporation efficiencies exceeding 80% could be achieved for these drugs. In-vitro release studies of these drugs were carried out in simulated gastric and intestinal fluids at 37°C. It was observed that the drug release rates were influenced by the cross-linking density, particle size and initial drug loading in the microspheres.
Pharmacological Evaluation of the Histamine H1 and 5-HT Blocking Properties of 2-N-(Carboxamidinonormianserin) (FCC5): in-vitro studies
Authors: Leitch Ian M , Boura Alan L A , King Roger G
Published: April 2011

Some in-vitro pharmacological effects of a novel analogue of mianserin, 2-carboxamidino-1,2,3,4,10,14b-hexahydrodibenzo (c,f) pyrazino (1,2,-α) azepine hydrochloride (FCC5) have been studied. FCC5 was a non-competitive antagonist of both histamine-induced contractions of the guinea-pig ileum and 5-HT-induced contractions of rat fundal strips with pD'2 values of 6·13 and 5·57, respectively. The insurmountable antihistaminic effect of FCC5, 100 Nm, in the guinea-pig isolated ileum was not removed by washing. FCC5, 10–100 Nm, had no effect on responses to acetylcholine or barium chloride of the guinea-pig isolated ileum. In guinea-pig isolated right atria, FCC5, 1–30 μm, had no effect on H2-receptor-mediated chronotropic responses to histamine. FCC5, 10–1000 Nm, had no α2-adrenoceptor antagonist activity, as assessed by lack of effect on the inhibitory responses to B-HT 920 in the electrically stimulated rat isolated vas deferens. FCC5 resembles mianserin by being a potent, non-competitive antagonist at histamine H1 and 5-HT receptors, but differs from mianserin in a number of respects including having much less effect at α2-adrenoceptors.
Non-opioid-dependent Inhibitory Action of Loperamide on Cholinergic Neurotransmission in Canine Isolated Bronchial Smooth Muscle
Authors: Tamaoki Jun , Horii Satsuki , Katayama Michio , Yamawaki Isao , Takizawa Takao
Published: April 2011

The effect of loperamide on cholinergic neurotransmission in canine bronchial smooth muscle was studied under isometric conditions in-vitro. Addition of loperamide decreased contractile responses to electrical field stimulation in a dose-dependent fashion, the maximal decrease from the control response and the IC50 value being 65·4 ± 5·9% and 1·5 μm, respectively. In contrast, loperamide was without effect on the responses to exogenously administered acetylcholine. The inhibitory effect of loperamide was not altered by pre-incubation of tissues with propranol, 6-hydroxydopamine, bicuculline, or naloxone. These results suggest that loperamide attenuates the neurally mediated airway contraction probably by inhibiting acetylcholine release from cholinergic nerve terminals through a non-opioid-dependent mechanism.
Stimulation of faecal excretion in rats by α2-adrenergic antagonists
Authors: Croci Tiziano , Bianchetti Alberto
Published: April 2011

The effects of several α-adrenoceptor antagonists on faecal output and water content in rats were investigated. Fed rats were treated either subcutaneously (s.c.) or orally with phentolamine, idazoxan, yohimbine, 1-(2-pyrimidinyl) piperazine (PmP) or prazosin. Drug potencies were compared on the basis of the dose inducing excretion of 1 g dry weight of faeces (AD1) by rats that do not normally excrete any faecal pellet during the observation time. The α2-antagonist, idazoxan (AD1 = 0·25 mg kg−1, s.c.) was approximately 2·5, 4 and 8 times more potent than PmP, phentolamine and yohimbine in promoting faecal excretion. Prazosin, an α1-antagonist with putative affinity for the α2B-receptor subtype, was the least effective (AD1 > 5 mg kg−1, s.c). The same compounds also increased the water content of faeces and had similar potencies by the oral route. Both clonidine (0·15 mg kg−1, s.c.) and atropine (0·2 mg kg−1, s.c.) significantly prevented the effects of all antagonists on faecal excretion. The present results are consistent with the view that rat colon is under tonic inhibitory control of prejunctional α2-adrenergic receptors, whose blockage by specific antagonists induces faecal excretion. The α2A-receptor subtype appears to be the most likely candidate for controlling faecal excretion through inhibition of acetylcholine release.
The potent irritancy of the daphnane orthoester, resiniferatoxin, exhibits features of a mixed aetiology
Authors: Evans A Tudor , Gordge Philip C , Sahni Vaneeta , Evans Fred J
Published: April 2011

Resiniferatoxin-induced erythema of mouse ear was shown to possess characteristics of both a phorbol ester-mediated response and that induced by the neurogenic irritant, capsaicin. Whereas the response to the phorbol ester, sapintoxin D, was delayed and prolonged, and was augmented by capsaicin pretreatment, the response to resiniferatoxin was biphasic, with the early phase being antagonized by capsaicin desensitization. However, resiniferatoxin was most potent in inducing a delayed erythema which, unlike the capsaicin response, was sensitive to inhibition by low dose hydrocortisone treatment, but not to chronic capsaicin desensitization. It is concluded that the erythema response to resiniferatoxin has a mixed aetiology, which may explain the unique potency of this toxin.
Quantitative Skin Blanching Assay of Corticosteroid Creams Using Tristimulus Colour Analysis
Authors: Chan Sui Yung , Po Alain Li Wan
Published: April 2011

The potencies of four proprietary corticosteroid creams were ranked using blanching measured by a tristimulus colour analyser as an index. Intra-subject variation was measured in a trial using a single subject while in a second study inter-subject variation was quantified using six volunteers. Discriminative parameters were derived from the extended multiple-point chromaticity coordinates L* and a* recorded after application of the steroid creams under occlusion. Analysis of variance of the data using the linear regression model was followed by Tukey's multiple comparison tests. Ranking of the creams using parameters of the pharmacodynamic response corresponded with the generally accepted rank order of the potencies of the corticosteroid creams. It is proposed that this multiple-point skin blanching assay of topical corticosteroids using an internationally accepted clear measurement standard and the subsequent data analysis be adopted as a standard protocol.
The Pharmacology of a Novel Topical Retinoid, BMY 30123: Comparison with Tretinoin
Authors: Tramposch K M , Nair X , Gendimenico G J , Tetrault G B , Chen S , Kiss I , Whiting G , Bonney R J
Published: April 2011

Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0·037 and 0·015 Mm, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours. While BMY 30123 and tretinoin are shown here to be equipotent in animal efficacy models, the low skin irritation activity gives BMY 30123, at a minimum, a 10-fold enhancement in the therapeutic index relative to tretinoin and suggests that retinoid efficacy and skin irritation are separable phenomena.
Parthenolide Content and Bioactivity of Feverfew (Tanacetum parthenium (L.) Schultz-Bip.). Estimation of Commercial and Authenticated Feverfew Products
Authors: Heptinstall S , Awang D V C , Dawson B A , Kindack D , Knight D W , May J
Published: April 2011

Three physicochemical methods (HPLC, NMR spectroscopy, and HPLC of a derivative) have been used to measure parthenolide in authenticated Tanacetum parthenium (feverfew) and in several commercial purported feverfew products. A bioassay based on inhibition of the secretory activity of blood platelets by extracts of feverfew in comparison with parthenolide was also used. Similar results were obtained for all three physicochemical assays and also for the bioassay. Thus different methodologies yield consistent values for parthenolide content of feverfew preparations. Parthenolide appears to be mainly responsible for the antisecretory effects of extracts of feverfew. Authenticated Tanacetum parthenium grown in the UK contained a high level of parthenolide in leaves, flowering tops and seeds but a low level in stalks and roots. The level of parthenolide in powdered leaf material fell during storage. The purported feverfew products varied widely in their parthenolide content and in some products parthenolide was not detected. Possible reasons for the variation in parthenolide content are discussed. Since therapeutic efficacy has only been demonstrated for preparations of feverfew that contain parthenolide, it is suggested that manufacturers of feverfew products should use measurements of parthenolide as a means of standardization and quality control.
Demonstration of the Receptor-mediated Hepatic Uptake of Dextran in Mice
Authors: Nishikawa Makiya , Yamashita Fumiyoshi , Takakura Yoshinobu , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

To establish a rationale of designing a drug targeting system using dextran conjugation, the disposition behaviour of dextran itself was investigated in mice. At a high dose (100 mg kg−1), [14C]dextran was retained in the blood circulation for a considerably long period. However, [14C]dextran rapidly disappeared from the plasma and accumulated in the liver (up to 60% of dose in 1 h) after a dose of 1 mg kg−1. Cellular localization of [14C]dextran in the liver following intravenous administration was examined and the contribution of parenchymal cells was demonstrated as well as the case of galactosylated bovine serum albumin (Gal-BSA). Pharmacokinetic analysis based on a physiological model including Michaelis-Menten type uptake mechanisms revealed that the Michaelis constant Km,l of [14C]dextran was 100 times greater than that of Gal-BSA. Coadministration of Gal-BSA delayed the hepatic uptake of [14C]dextran and the simulation based on the physiological model suggested that [14C]dextran was taken up by the same mechanism as Gal-BSA. These results suggested that dextran conjugation of a drug might lead to its undesirable accumulation in the liver at a low dose and an appropriate modification of dextran, such as carboxymethylation, would be required in such cases.
Interaction and Aggregation of Sodium Aurothiomalate and Poly l-Lysine
Authors: Brown Robert A , Wells Terri M
Published: April 2011

This report describes the interaction and aggregation of sodium aurothiomalate with polylysine, a potentially useful property, both as a model for drug-protein interaction and as a means of reversibly immobilizing sodium aurothiomalate. Sodium aurothiomalate formed stable precipitates with polylysine at neutral pH, ionic strengths below 1m NaCl, and optimally, at sodium aurothiomalate to lysine ratios of less than one. The interaction could be demonstrated both by precipitation (which was sensitive to the size of polylysine polymer) and by using polylysine immobilized to Sepharose. Precipitation could be inhibited by addition of the organic thiomalate moiety alone. These findings indicate that the interaction of sodium aurothiomalate with polylysine is by electrostatic bonding of the thiomalate (mercaptosuccinate) moiety and the ε-amino groups of lysine residues. At suitable molar ratios this will link together many polylysine chains leading to precipitation. This represents a potentially valuable interaction for immobilization of the drug and in the formation of conjugates.
Doxorubicin-loaded Casein Microspheres: Protean Nature of Drug Incorporation
Authors: Willmott N , Magee G A , Cummings J , Halbert G W , Smyth J F
Published: April 2011

We have studied incorporation of [14C]doxorubicin within protease-sensitive casein microspheres both by 14C-activity, measuring total drug, and HPLC, measuring free drug only. It was found that total drug content (27·7 μg mg−1) exceeded free drug content (3·2 μg mg−1) suggesting that the major portion of doxorubicin was incorporated via a covalent linkage to matrix protein. In-vivo drug disposition and activity studies suggested that this fraction of doxorubicin was the major species within tumour tissue (total vs free: 5 min, 14·3 μg g−1 vs 0·7 μg g−1; 24 h, 11·7 μg g−1 vs 1.1 μg g−1;48 h, 11·2 μg g−1 vs 1·2 μg g−1; 72 h, 100 μg g−1 vs 0·8 μg g−1), did not exhibit a ‘burst’ effect, was slowly cleared (30% loss over 3 days), and was equiactive (growth delay = 12 days) compared with drug in solution (growth delay = 10 days). This work clearly implicates in-vivo microsphere matrix biodegradation in drug release and subsequent disposition and activity.
Anti-ulcer Activity of a Slow-release Zinc Complex, Zinc Monoglycerolate (Glyzinc)
Authors: Rainsford K D , Whitehouse M W
Published: April 2011

A slow-release zinc complex, zinc monoglycerolate (ZMG) was examined for its potential gastroprotective activity in various gastric ulcer models. These models comprised (a) oral or parenteral nonsteroidal anti-inflammatory drugs (NSAIDs) given to rats whose gastrointestinal mucosa was pre-sensitized by prior development of arthritis, oleyl alcohol-induced inflammation and cold exposure, (b) oral ethanol (12·5−100%) with and without added 4% HCl, (c) intraperitoneal reserpine (5 mg kg−1) in arthritic and normal rats and in normal mice, (d) oral NSAIDs given to mice in which acid and pepsin production was stimulated by co-administration of intraperitoneal bethanechol chloride (5 mg kg−1) to enhance ulcer development, and (e) NSAIDs given to carrageenan-inflamed rats to determine effects of ZMG on paw inflammation. In these models, ZMG given orally was effective in preventing development of gastric lesions, except with propionic acid NSAIDs; the effective doses being apparently dependent on the severity of the mucosal injury. In many of the models ZMG was superior to zinc sulphate and other zinc salts or metal ion complexes investigated but was slightly more effective or equipotent compared with zinc acexamate. ZMG did not impair the anti-oedemic effects of NSAIDs. ZMG is thus an effective agent in preventing ulcer development in a wide range of model systems and may be more effective than zinc salts because of the controlled slow-release of zinc from the complex.
Characteristics of Procarbazine as an Inhibitor In-vitro of Rat Semicarbazide-sensitive Amine Oxidase
Authors: Holt Andrew , Sharman Dennis F , Callingham Brian A , Kettler Rolf
Published: April 2011

Procarbazine (N-isopropyl-α-(2−methyl hydrazino)-p-toluamide hydrochloride) inhibited more powerfully the deamination of benzylamine by semicarbazide-sensitive amine oxidase (SSAO) of rat brown adipose tissue than the deamination of 5−hydroxytryptamine and benzylamine by rat liver monoamine oxidase-A or -B activities, respectively. Inhibition of SSAO, but not monoamine oxidase, was time-dependent. Use of metabolic inhibitors, and an enzyme dilution technique, suggested that any conversion of procarbazine to an active species must be as a result of the action of SSAO itself and not of any other enzyme. The non-competitive kinetics and the time-dependence of inhibition were indicative of a suicide interaction between procarbazine and SSAO. The slow reversal of inhibition by dialysis was evidence in favour of the involvement of tight binding, rather than covalent bonding. High concentrations of benzylamine afforded the enzyme significant protection from the action of procarbazine, indicating that the interaction is at or near the active site. If the properties of procarbazine, evident in in-vitro studies, are retained in-vivo, these data suggest that procarbazine might be suitable for the examination of SSAO activities, both in-vivo and ex-vivo.
Effects In-vitro of Procarbazine Metabolites on Some Amine Oxidase Activities in the Rat
Authors: Holt Andrew , Sharman Dennis F , Callingham Brian A
Published: April 2011

The effects were examined of four metabolites of the anticancer agent, procarbazine (N-isopropyl-α-(2−methyl hydrazino)-p-toluamide hydrochloride) on semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase-A and -B (MAO-A and -B) activities in rat brown adipose tissue and liver homogenates, respectively. Azoprocarbazine (AZO) and monomethylhydrazine (MMH) inhibited selectively the deamination of benzylamine by SSAO, when compared with their effects on MAO activities. The IC50 values against SSAO, of 32·7 Nm (AZO) and 7·0 Nm (MMH), were more than three orders of magnitude lower than those exhibited against MAO. Neither isomer of azoxyprocarbazine was an effective inhibitor of rat amine oxidase activities. The inhibition of SSAO by AZO was reversed very slowly by dialysis, in contrast to results seen for MMH. The non-competitive kinetics of MMH and the ability of B24, a rapidly reversible SSAO inhibitor, to protect SSAO against inhibition by MMH are consistent with the view that this compound binds to the enzyme cofactor at, or near, the active site.
Effect of ryanodine on histamine release from rat peritoneal mast cells induced by anti-IgE
Authors: Takei Masao , Ueno Mokoto , Endo Koichi
Published: April 2011

Ryanodine strongly inhibited histamine release from rat peritoneal mast cells induced by anti-IgE. Ryanodine also inhibited Ca2+-mobilization from the intracellular Ca2+-store as well as histamine release in mast cells activated by anti-IgE. These results suggest that the effect of ryanodine on histamine release from rat mast cells might be due to the inhibition of Ca2+ release from the intracellular Ca2+ store.
Supersensitivity to morphine after chronic sympathetic denervation in guinea-pig colon
Authors: Marino F , Marcoli M , Lecchini S , Frigo G M
Published: April 2011

The possible role of opioid systems in the adaptive changes which follow chronic sympathetic denervation in the guinea-pig colon has been studied by comparing the effects of the opioid agonist morphine in control animals and after chronic sympathetic denervation. Supersensitivity to the inhibitory effects of morphine on the peristaltic reflex was observed after chronic sympathetic denervation, while the potency against acetylcholine release was unmodified. Our results suggest that a modification of the opioid system occurs after sympathetic denervation in the guinea-pig colon. Supersensitivity to endogenous opioids at a site different from that regulating acetylcholine release could account for the counter-regulation of intestinal motility after chronic sympathetic denervation.
Sulphasalazine fails to prevent development of mucosal ulceration and 5-lipoxygenase activity in guinea-pigs with chronic inflammatory bowel disease induced by combined bacterial immunization and oral carrageenin
Authors: Oestreicher P , Nielsen S T , Rainsford K D
Published: April 2011

A model of inflammatory bowel disease in guinea-pigs involving a 14 day initial treatment with formalin-killed Bacteroides vulgatus subcutaneously and oral carrageenin plus live B. vulgatus for 10 days was used to determine the effects of sulphasalazine 100 mg kg−1 day−1 b.i.d., p.o. given for 4, 7 and 10 days after cessation of the bacterial/carrageenin treatment on the morphological and histological states of the established disease and on the production of the principal 5−lipoxygenase products, 5−hydroxyeico-satetraenoic acid and leukotriene B4. The drug treatment did not cause any significant changes in this established disease as measured by these parameters.
Influence of changes in protein binding on the central activity of antidepressants
Authors: Torres I , Gomez E , Garcia E , Suárez E , Rodriguez-Sasiaín J M , Calvo R
Published: April 2011

The central effect (expressed as analgesic response), protein binding and brain uptake of mianserin were measured in mice receiving drug intraperitoneally. A significant decrease of the central effect of mianserin (30 mg kg−1) was seen in mice with experimental inflammation when compared with control animals (reaction time (s)= 12·12 ± 1·22 vs 25·56 ± 2·92; P < 0·001) and the dose-analgesia response curve (10−60 mg kg−1) was significantly shifted to the right in mice with inflammation. In serum of mice with inflammation, unbound concentration of mianserin was decreased from 19·37 ± 0·73 to 17·83 ± 0·30% (P < 0·05) and seromucoid levels were significantly increased (P < 0·001). Following the intraperitoneal administration of 30 mg kg−1 of mianserin, brain uptake decreased in diseased mice when compared with control animals (P < 0·02), suggesting that the decrease in analgesia was secondary to a decrease in drug delivery to the brain because of increased protein binding.
Hydrolysis Kinetics of Phospholipids in Thermally Stressed Intravenous Lipid Emulsion Formulations
Authors: Herman C J , Groves M J
Published: April 2011

A model 20% w/v emulsion, prepared with either a commercially available pharmaceutical grade soy oil or a highly purified grade of oil from the same origin and stabilized with a commercially available mixture of egg yolk phospholipids was passed through a Microfluidics homogenizer until the mean particle size fell below 500 nm diameter. Samples stored in sealed all-glass ampoules were thermally stressed over a temperature range of 5–90°C and samples taken at appropriate intervals for analysis by HPLC. Hydrolysis degradation kinetics were in conformation with the Arrhenius equation. The energy of activation for phosphatidylcholine was virtually identical for emulsions prepared with either pharmaceutical or purified oil (65 and 63 kJ mol−1, respectively). For phosphatidylethanolamine itself the respective activation energies were 53 and 54 kJ mol−1, suggesting that the source of the oil used in preparing the emulsions had no significance in the degradation processes of the resulting systems.