bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Dopaminergic and Noradrenergic Systems on the Release of Opioid Peptides in Guinea-pig Ileum
Authors: Milanés M Victoria , Martínez J Antonio , Vargas M Luisa
Published: April 2011

Neuroleptic drugs increase the biosynthesis and release of opioid peptides from the myenteric plexus of guinea-pig ileum. In the present work, the involvement of dopamine receptors or α-adrenoceptors in the release of opioids from the myenteric plexus of guinea-pig was investigated. Acute or chronic treatment with prazosin, an α1-blocking drug, produced no changes in the release of these peptides. Release was also unchanged after acute or chronic treatment with the α2-blocking drug yohimbine. However, treatment with domperidone, a selective dopamine receptor antagonist, resulted in an increase in the release of opioids, as did treatment with (-)−3−(3−hydroxyphenyl)-N-n-propylpiperidine ((-)−3−PPP), a dopamine autoreceptor stimulant. It is concluded that the effect of neuroleptics on the release of opioids from myenteric plexus is due to the blockade of dopamine receptors, and that interruption of dopaminergic transmission produces an increase in opioid release at this level.
Putrescine reverses aconitine-induced arrhythmia in rats
Authors: Bazzani Carla , Genedani Susanna , Tagliavini Simonetta , Bertolini A
Published: April 2011

Putrescine, (150–300 mg kg−1 i.v.) injected into anaesthetized rats reversed aconitine-induced arrhythmia and restored sinus rhythm. In the same experimental model, quinidine and lignocaine had a transient therapeutic effect, procainamide was practically ineffective and verapamil worsened the aconitine arrhythmia, causing the death of all treated animals. These data demonstrate that putrescine has an antiarrhythmic effect in an experimental model particularly resistant to usual antiarrhythmic treatments.
Moisture Sorption Profiles and Tensile Strength of Tableted Phenobarbitone Formulations
Authors: Malamataris S , Dimitriou A
Published: April 2011

The tensile strength of tablets made from phenobarbitone and sodium phenobarbitone formulations after storage at increasing ambient relative humidity has been investigated. The moisture sorption and desorption profiles of the formulations were analysed for three locations of moisture: monolayer adsorbed moisture, normally condensed moisture and absorbed moisture. Maxima in tensile strength occur at moisture distributions determined by the disintegrant used. The changes in tensile strength have been explained in terms of changes produced in the interparticle separation, the range of the interparticle forces and changes in the ratio of the binding to diffusional forces, acting on the water molecules which are on the particles' surface.
Comparative Drug Exsorption in the Perfused Rat Intestine
Authors: Huang Jin-Ding
Published: April 2011

The factors affecting drug exsorption into the gastrointestinal tract are uncertain. In this study, the intestinal clearance (CLi) of compounds which vary in their lipophilicity, serum protein binding, molecular weight and ionic charge at physiological pH, has been measured. Male Sprague-Dawley rats with ligated bile ducts were infused with the test compounds through the jugular vein. The small intestine was intubated and perfused with Tyrode solution at 20 mL h−1. The CLi of the compounds investigated (urea, polyethylene glycol, inulin, albumin, dextran, barbituric acid, salicylic acid, thiobarbital, thiopental, thioseconal, theophylline, S-disopyramide and quinidine) was determined under anaesthesia by dividing the rate of a component's appearance rate in the perfusate by its carotid arterial concentration. Serum protein binding of the compounds was determined by equilibrium dialysis. The n-octanol-water partition coefficients of the compounds were measured as indices of lipophilicity. The CLi values of dextran, albumin, inulin, polyethylene glycol and urea were 0.56, 1.03, 4.5, 4.8 and 12.0 mL h−1, respectively. The larger the molecular weight of a compound, the smaller its CLi. The molecular weight is apparently one of the major determinants of CLi. Thiobarbital, thiopental and thioseconal are compounds of similar structure with increasing lipophilicity and serum protein binding. The CLi of thiobarbital, thiopental and thioseconal was proportional to the unbound fraction in serum. The unbound clearance (CLui) of three thiobarbiturates were similar (∼ 11 mL h−1). The unbound fraction of drug in serum appears to be a factor determining their CLi. Barbituric acid and salicylic acid, two acidic compounds, showed a low CLi (< 1 mL h−1). In contrast with barbituric acid and salicylic acid, the CLi of theophylline, S-disopyramide and quinidine was much higher (> 30 mL h−1). The CLi of dextran, thiopental or S-disopyramide was not affected by altered perfusion rate. Other than molecular weight and serum protein binding, the ionic charge of compounds at physiological pH was the most significant factor affecting CLi. The lipophilicity of compounds and the perfusion rate did not seem to be important factors.
Modulation of the GABAA Receptor by Barbiturates and Pregnane Steroids: Differential Effects of the Influence of Assay Temperature
Authors: Yau J L W , Balfour D J K , Stevenson I H
Published: April 2011

The effect of temperature on the modulation of the GABAA receptor by barbiturates and steroids has been investigated in-vitro using a radioreceptor binding assay. Displaceable [3H]muscimol binding to a crude membrane preparation from rat cerebral cortex was enhanced by the endogenous steroid metabolite, 5β-pregnan-3α-ol-20-one, by the synthetic steroid, alphaxalone, and by pentobarbitone in a dose-dependent manner. Hydrocortisone and corticosterone had no significant effect on [3H]muscimol binding. Analysis of binding data using a curve-fitting program (‘Ligand’) showed that both pentobarbitone (1 mM) and 5β-pregnan-3α-ol-20-one (10 μM) increased the apparent number of high affinity binding sites in the membrane but had no effect on the affinity of [3H]muscimol binding (Kd approx. 11 nM). Increasing the assay temperature from 0°C to 35°C decreased [3H]muscimol binding and decreased the enhancement of binding by pentobarbitone but had no effect on 5β-pregnan-3α-ol-20-one enhancement of binding. 5α-Pregnan-3α-ol-20-one increased the apparent rate of association of [3H]muscimol binding to its receptor whereas pentobarbitone had no effect. These different effects on the apparent association rate and the different responses to temperature, suggest that the barbiturate and steroid may interact with the GABAA receptor through different binding sites.
Characterization of cysteinyl-leukotriene formation in primary astroglial cell cultures
Authors: Seregi András , Simmet Thomas , Schobert Angelika , Hertting Georg
Published: April 2011

The formation and composition of cysteinyl-leukotrienes (LT) in primary astroglial cell cultures prepared from newborn rat brain has been studied. Small amounts of cysteinyl-LT determined in terms of LTC4-like material in the supernatants of the cultures, became detectable after stimulation of the cells with 10−5 M ionophore A23187. Cysteinyl-LT formation increased with time, reaching about 600 pg (mg protein)−1 after 60 min incubation. In contrast, considerable thromboxane (TX) B2 synthesis was found at 5 min following A23187-stimulation (about 30 ng TXB2 (mg protein)−1). The synthesis of cysteinyl-LT was abolished by 5 × 10−5 M nordihydroguaiaretic acid (NDGA). Irrespective of the duration of incubation, blockage of prostanoid synthesis by 10−6 M indomethacin did not result in increased cysteinyl-LT production. Reversed phase HPLC combined with radioimmunological detection showed that, after 60 min incubation in the presence of A23187, LTC4 and LTD4 accounted for practically all the LTC4-like immunoreactive material in the supernatants of cell cultures. No significant amounts of LTE4 could be detected. The results show that astrocytes may contribute to brain LTC4 and LTD4 synthesis. However, the cellular site of cerebral LTE4 formation seems to be other than the astroglia.
Glycyrrhetinic acid derivatives: Anti-nociceptive activity of deoxoglycyrrhetol dihemiphthalate and the related compounds
Authors: Inoue Hideo , Kurosu Shinobu , Takeuchi Tadao , Mori Takeo , Shibata Shoji
Published: April 2011

The possible inhibitory effect of deoxoglycyrrhetol dihemiphthalate (I) and the related compounds (18β-olean-9(11), 12-diene-3β,30-diol) (II) and (olean-11,13(18)-diene-3β,30-diol) III derived from glycyrrhetinic acid has been examined on acetic acid-induced writhing in mice. The compounds inhibited writhing dose-dependently. Their ED50 values were 14,31 and 22 mg kg−1 for I, II, and III, respectively. The compounds like aspirin, also significantly suppressed PGE2 production in peritoneal fluid together with the writhing response. The results suggests that the analgesic effect of deoxoglycyrrhetol dihemiphthalate and the related compounds is partially due to inhibition of PGE2 production.
Choline is an inhibitory modulator of cholinergic nerve function in guinea-pig colon
Authors: Trout S J , Burleigh D E
Published: April 2011

Using the novel smooth muscle-myenteric plexus (smmp) preparation from the guinea-pig colon, it has been possible to measure acetylcholine (ACh) overflow by a radiolabelling technique. The possibility that choline may be a modulator of cholinergic nerve activity in this preparation was investigated by observing its effects on electrically-evoked overflow of [3H]acetylcholine. Choline (72, 144 μM), in concentrations that did not contract the smmp preparation, caused a depression of electrically-evoked [3H]ACh overflow. This effect was unlikely to be due to actions on cholinesterase enzymes by end product inhibition. Choline also produced substantial non-muscarinic elevation of spontaneous [3H]overflow. It is concluded that inhibitory modulation of enteric cholinergic nerve activity by presynaptic muscarinic receptors may not be exclusively mediated by the actions of acetylcholine.
Ability of ketanserin to block different receptors in human placental vessels
Authors: Marin Jesus , Reviriego Jesus , Fernandez-Alfonso Maria S
Published: April 2011

5-Hydroxytryptamine (5-HT), noradrenaline (NA) and histamine induced concentration-dependent contractions in segments of human chorionic arteries and veins, whereas clonidine, an α2-adrenoceptor agonist, had no effect. 5-HT and histamine induced strong contractions, while NA elicited weak contractions in some segments. The maximal response was similar for 5-HT and histamine. The order of potency (EC50 values) was: 5-HT ≥ NA ≥ histamine. These agonists induced tachyphylaxis, and single concentrations caused transient contractions. Contractions elicited by 5-HT were antagonized by ketanserin, a 5-HT2-receptor antagonist, which also antagonized the responses to NA and histamine, but at greater concentrations than those needed for 5-HT responses. Contractions elicited by histamine were reduced by diphenydramine. Low concentrations of 5-HT amplified contractions caused by NA and histamine. The results indicate that: (i) 5-HT is the most potent constrictor agent tested in these vessels; (ii) its effects are mediated by 5-HT2-receptors; and (iii) ketanserin at therapeutic plasma concentrations (10−7 M) seems to block mainly 5-HT2-receptors, and α1-adrenergic- and H1-receptors to a small extent only.
β-Adrenoceptor antagonists and human sperm motility
Authors: Curtis-Prior P B , Gadd A L
Published: April 2011

Several β-adrenoceptor blocking agents have been evaluated for spermicidal activity using a transmembrane migration method. The rank order of potency of the active compounds was: penbutolol > (+) - propranolol > bufuralol > (—) - alprenolol > oxprenolol > metoprolol. Atenolol, pindolol, practolol, tolamolol were without activity. The observed potencies of spermicidal activity are believed to be unrelated to β-blocking activities, and we have shown that whilst they are not predictable from lipid solubility or nonspecific membrane properties of the compound alone, both these aspects appear to play a role in this pharmacological activity.
Detection of Poly(I): Poly(C12U), Mismatched Double-stranded RNA, by Rapid Solution Hybridization: Blood Values after Intravenous Infusion
Authors: Strauss K I , Strayer D R , Gillespie D H
Published: April 2011

A rapid solution hybridization technique has been developed for estimating blood concentrations of poly(I):poly(C12U), a high molecular weight bioactive double-stranded RNA. Samples were prepared by mixing 100 μL of blood with, 165 μL of 6 M guanidine thiocyanate (GuSCN) and 0.16 M EDTA pH 8.0, and freezing. Hybridizations were carried out with a [3H]poly(C) probe in 3 M GuSCN for 10 min at 37°C. Ribonuclease-resistant hybrids were collected by precipitation with trichloroacetic acid and filtration. Validation studies demonstrated minor interassay variance; the assay was accurate in the range 0.1 to 10 ng poly(I):poly(C12U). Thirty-one blood samples from 15 patients were collected and prepared before and immediately after an average 35 min intravenous infusion of 40–500 mg poly(I):poly(C12U). Postadministration values averaged 48% (s.d. 23%) of the theoretical maximum (range 20–102%). These results confirm previous observations of rapid elimination kinetics of poly(I):poly(C12U) in patients.
Species-dependent differences in the properties of particulate cyclic nucleotide phosphodiesterase from rat and rabbit ventricular myocardium
Authors: Shahid M , Wilson M , Nicholson C D , Marshall R J
Published: April 2011

The ability of cyclic nucleotide phosphodiesterases (PDEs) to hydrolyse cyclic (c)AMP in rat and rabbit ventricular myocardium has been compared. The PDE activity of rabbit, but not rat, cardiac homogenate and supernatant fraction was potentiated by Ca2+/calmodulin and attenuated by cGMP. Both rabbit and rat ventricular myocardium were shown to have a membrane bound PDE. However, rabbit membrane-bound PDE was inhibited by cGMP and low concentrations of milrinone (IC50 2.7 μM). In contrast, rat membrane-bound PDE was not inhibited by either cGMP or low concentrations of milrinone (IC50 19 μM), but it was potently inhibited by rolipram (IC50 2.2 μM). Thus, in rabbit the particulate PDE is milrinone sensitive (PDE III) whilst in rat it is the rolipram sensitive (PDE IV) isoenzyme. There are clearly species differences in the intracellular localization and relative activities of PDE isoenzymes in cardiac tissue. This may explain the species differences already found in the activity of selective PDE isoenzyme inhibitors as inotropic agents.
Antidiabetic and aldose reductase activities of biflavanones of Garcinia kola
Authors: Iwu Maurice M , Igboko Ogo A , Okunji Chris O , Tempesta Michael S
Published: April 2011

Kolaviron, a mixture of C-3/C-8 linked biflavonoids obtained from Garcinia kola produces significant hypoglycaemic effects when administered intraperitoneally to normal and alloxan diabetic rabbits at a dose of 100 mg kg−1. The fasting blood sugar in normoglycaemic rabbits was reduced from 115 mg/100 mL to 65 mg/100 mL after 4 h. In alloxan diabetic rabbits, the blood sugar was lowered from 506 mg/100 mL to 285 mg/100 mL at 12 h. The hypoglycaemic effects have been compared with those of tolbutamide. Kolaviron inhibited rat lens aldose reductase (RLAR) activity, with an IC50 value of 5.4 × 10−6. The significance of these findings in the potential use of kolaviron as an antidiabetic agent is discussed.
Insulin absorption from conjunctiva studied in normal and diabetic dogs
Authors: Nomura M , Kubota M A , Sekiya M , Hoshiyama S , Imano E , Matushima Y , Ishimoto I , Kawamori R , Kamada T
Published: April 2011

The dynamics of insulin absorption from the ocular conjunctiva of anaesthetized normal and pancreatectomized dogs have been examined. A porcine insulin preparation of 1000 units mL−1 (pH 8.0) was administered as either 1 or 10 units kg−1 to the upper conjunctival sacs of recumbent dogs following an overnight fast. Plasma insulin concentrations increased significantly at 5 min after the insulin administration. Plasma glucose concentrations decreased significantly, in both normal (given 10 units kg−1) and diabetic dogs (given 1 unit kg−1 or 10 units kg−1). There was a dose-dependent increase in plasma insulin concentration following conjunctival administration. Estimated absorption was significantly higher in diabetic than in normal dogs.
Antihistaminic activity of pulegone on the guinea-pig ileum
Authors: de Urbina A V Ortiz , Martin M L , Montero M J , Carron R , Sevilla M A , San Roman L
Published: April 2011

Pulegone, a natural monoterpene compound, has an antihistamine effect on guinea-pig ileum. Its antagonism is of the competitive type (PA2 = 6.35) like that of mepyramine and dexchlorpheniramine, two H1-antagonists, with PA2 values of 10.15 and 8.74, respectively.
Correlation Between Structures of Organic Cations and Their Binding Behaviours to Brush Border Membrane Isolated from Rat Small Intestine
Authors: Saitoh Hiroshi , Noujoh Akiko , Chiba Yukihiro , Iseki Ken , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

We have investigated the correlation between the molecular structures of various organic cations and their binding to rat small intestinal brush border membrane. The binding of small quaternary ammonium compounds such as tetramethylammonium and choline to brush border membrane was not sufficient to inhibit methylchlorpromazine binding. However, lauryltrimethylammonium and cetyltrimethylammonium, both quaternary amines with a long carbon chain, inhibited binding significantly. The inhibition was competitive. When the unbranched hydrocarbon chain of the quaternary amines was extended in steps from C1 (methyl) to C16 (cetyl), the inhibitory effect increased sharply with length from C7 (heptyl) to C16. These results suggest that the size of the hydrophobic part of the molecule is an important factor in binding of quaternary ammonium compounds to the brush border membrane. The structure of the hydrophilic part was another factor. In imipramine-related compounds, the order of binding was N-didesmethylimipramine (primary amine) > desipramine (secondary) > imipramine (tertiary) > methylimipramine (quaternary). However, with the small molecular ethylamine-related compounds, binding properties did not reflect differences in the hydrophilic component. Therefore, the effect of the hydrophilic part may be secondary and may depend on the size of the hydrophobic part. We suggest that organic cations which are amphiphilic can bind to a common binding site on brush border membrane through hydrophobic and/or hydrophilic interactions.
Contribution of Passive Transport Mechanisms to the Intestinal Absorption of β-Lactam Antibiotics
Authors: Sugawara Mitsuru , Saitoh Hiroshi , Iseki Ken , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

The transport characteristics of aminopenicillins (ampicillin and amoxicillin), aminocephalosporins (cephalexin, cephradine and cefadroxil) and cefazolin have been compared with those of an actively transported substance (D-glucose) and a passively transported substance (L-glucose). Although the initial uptake of the aminocephalosporins was stimulated in the presence of an inward H+ gradient, there was no overshoot in the uptake of any of the drugs tested, even in the presence of an H+ gradient. Also, the time course and the degree of uptake of these drugs were similar to those of L-glucose, especially in the absence of an H+ gradient. These results suggest that the β-lactam antibiotics tested, like L-glucose, pass through the rat intestinal brush border membrane mainly by passive diffusion. However, the differences in absorption between these drugs, like the differences in their disappearance from a proximal loop of rat intestine, cannot be explained by a simple permeation process alone.
The Effects of (±)-, (+)- and (-)-Celiprolol and Bromoacetylalprenololmentane at the β-Adrenoceptors of Rat Isolated Cardiovascular Preparations
Authors: Doggrell Sheila A
Published: April 2011

The effects of (±)-, (+)- and (-)-celiprolol and of bromoacetylalprenololmentane (BAAM, an irreversible β-adrenoceptor antagonist) on the contractile responses of the electrically driven rat right ventricle strip to isoprenaline and on the relaxant responses of the rat aorta to procaterol, have been studied. Racemic and (-)-celiprolol or BAAM treatment of the ventricle produced non-parallel rightward shifts of the isoprenaline response curves with a reduction in the maximal response. Sotalol produced parallel rightward displacements of the procaterol response curves of the aorta with no effect on the maximal relaxations. Racemic and (+)- and (-)-celiprolol or BAAM treatment of the aorta produced non-parallel rightwards shifts of the procaterol relaxant curves with a reduction in the maximal relaxation. The BAAM data was used to demonstrate that the KA (dissociation constant) for isoprenaline at β1-adrenoceptors was 1.46 × 10−7 M and for procaterol at β2-adrenoceptors was 2.34 × 10−5 M. Calculation of receptor occupancy demonstrated that to produce a maximal response of the rat right ventricle, isoprenaline had to occupy 87% of the β1-adrenoceptors. Likewise, for a maximal response of the rat aorta, procaterol had to occupy 81 % of the β2-adrenoceptors. It is suggested that the use of tissues with small β-adrenoceptor reserves has shown that (±)- and (-)-celiprolol are slowly dissociating, rather than readily reversible, β-adrenoceptor antagonists.
The effect of loperamide oxide on prostaglandin-stimulated fluid transport in rat small intestine
Authors: Hardcastle J , Hardcastle P T , Goldhill J
Published: April 2011

The effects of loperamide and loperamide oxide on basal and prostaglandin Erstimulated fluid transport by rat small intestine have been investigated. In contrast to loperamide, loperamide oxide, when applied intraperitoneally, failed to inhibit either basal or prostaglandin E2-stimulated fluid transport. However, intraperitoneal administration of loperamide oxide following its incubation with the contents of the intestinal lumen under aerobic conditions resulted in an effective inhibition of fluid secretion. The activating material was present in the essentially non-particulate 3000 g supernatant fraction of the luminal contents and was heat-stable.
Endothelin action on goat cerebral arteries
Authors: Vila J M , de Aguilera E Martin , Martinez M C , Rodriguez M D , Irurzun A , Lluch S
Published: April 2011

Cumulative application of endothelin-1 (human) markedly constricted goat isolated cerebral arteries in a concentration-dependent manner. Contractile responses were not affected by removal of endothelial cells. Removal of extracellular calcium or addition of the calcium channel blocker nicardipine (10−7 M) failed to abolish responses to endothelin. The results suggest that the endothelium-independent constriction of cerebral arteries produced by endothelin cannot be explained solely by voltage-dependent calcium channels. The contractile responses are likely to be mediated by stimulation of specific receptors for this peptide.
Calcium Antagonist Properties of Cinnarizine, Trifluoperazine and Verapamil in Guinea-pig Normal and Skinned Trachealis Muscle
Authors: Cortijo J , Foster R W , Small R C , Morcillo E J
Published: April 2011

In guinea-pig trachealis, depolarized by a K+ -rich medium, Ca2+ (0.01–10 mM) caused concentration-related spasm. Verapamil (0.5-5 μM), cinnarizine (10–100 μM) and trifluoperazine (16–160 μM) each produced concentration-dependent antagonism of Ca2+ characterized by a rightward and downward displacement of the log concentration-effect curve for Ca2+. The rank order of potencies of these antagonists, measured as the IC75 against Ca2+ (10 mM)-induced contraction of depolarized trachea, was verapamil (5.6 μM) > cinnarizine (59 μM) > trifluoperazine (91 μM). In skinned trachea, verapamil in concentrations up to 100 μM did not modify the concentration-effect curve for Ca2+. In contrast, cinnarizine (59–177 μM) diminished the sensitivity and trifluoperazine (273 μM) decreased the responsiveness of the tissue to Ca2+. In skinned trachea, trifluoperazine (91 μM) produced greater inhibition of Ca2+ (10 μM)-induced contraction after 120 min than after 30 min of incubation. Verapamil (100 μM) and cinnarizine (177 μM) were devoid of inhibitory effect against the 10 μM Ca2+ standard. In skinned trachea, changes in the Ca2+ concentration-effect curve produced by cinnarizine (177 μM) were reversed after washout whilst those induced by trifluoperazine (273 μM) persisted. It is concluded that distinct differences exist between the three calcium antagonists examined. The action of verapamil is restricted to the plasmalemma. That of cinnarizine and trifluoperazine is exerted both on the plasma membrane and upon the intracellular contractile machinery.
The Effect of Malaria Infection on the Disposition of Quinine and Quinidine in the Rat Isolated Perfused Liver Preparation
Authors: Mansor S M , Ward S A , Edwards G , Hoaksey P E , Breckenridge A M
Published: April 2011

The effect of malaria on the disposition of quinine and quinidine was studied in livers isolated from young rats infected with merozoites of Plasmodium berghei, a rodent malaria model, and non-infected controls. Following bolus administration of quinine (1 mg) or quinidine (1 mg) to the 100 mL recycling perfusion circuit, perfusate was sampled (0–4 h) and plasma assayed for quinine and quinidine by HPLC. Higher quinine (AUC: 6470 ± 1101 vs 3822 ± 347 ng h mL−1, P < 0.001) and quinidine (AUC: 6642 ± 1304 vs 4808 ± 872 ng h mL−1, P < 0.05) concentrations were observed during malaria infection (MI). MI resulted in decreased quinine clearance (CL) (0.33 ± 0.08 vs 0.64 ± 0.09 mL min−1 g−1, P < 0.001) and volume of distribution (Vd) (53.0 ± 13.3 vs 81.2 ± 23.7 mL g−1, P < 0.05) but no significant change in elimination half-life (t1/2) (1.93 ± 0.6 vs 1.37 ± 0.25 h, P > 0.05). With quinidine, however, MI resulted in decreased CL (0.38 ± 0.16 vs 0.64 ± 0.09, P < 0.05) with no change in Vd and a significant increase in t1/2 (1.62 ± 0.42 vs 0.88 ± 0.22, P < 0.01). In summary, the hepatic disposition of quinine and quinidine is altered in the malaria-infected rat.
JO 1784, a potent and selective ligand for rat and mouse brain σ-sites
Authors: Roman François J , Pascaud Xavier , Martin Brigitte , Vauché Daniel , Junien Jean-Louis
Published: April 2011

JO 1784 ((+)-cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene) is a potent ligand for (+)-[3H]SKF 10,047 (2′-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan) binding sites in rat brain membrane preparations with an IC50 of 39 ± 8 nM, which is comparable to that of haloperidol. The stereoisomer of JO 1784 is ten fold less potent. When administered to mice i.p. or p.o. JO 1784 displaced (+)-[3H]SKF 10,047 (5 μCi i.v.) from its sites in the brain with ID50 values of 1.2 and 3.5 mg kg−1, respectively. The high selectivity of JO 1784 for the σ-binding site was assessed by its lack of significant affinity for more than 20 other sites including those for phencyclidine.
Comparison of the inhibitory action of aminobeclamide and beclamide on socially offensive behaviour
Authors: Darmani N A , Sewell R D E , Hasan M Y , Nicholls P J
Published: April 2011

The inhibitory effects of aminobeclamide (N-(p-aminobenzyl)-β-chloropropionamide) on socially offensive behaviour has been studied and compared with those of the parent drug beclamide (N-benzyl-β-chloropropionamide). Following oral administration in mice which had been individually housed for a 28 day period then paired with normal group-housed opponents, aminobeclamide and beclamide both produced significant and dose-related inhibition of socially offensive behaviour. Aminobeclamide (20–150 mg kg−1 p.o.) and beclamide (50–250 mg kg−1 p.o.) gave increased offense onset latency whilst at the same time they reduced the incidence of offense encounters/animal and decreased the group percentage of animals displaying offense behaviour. It is likely that both drugs have similar monoamine modifying effects though this animal study suggests that aminobeclamide is 1.5 to 2.7 times more potent than beclamide against socially offensive behaviour.
A rapid gas-liquid chromatographic method for the determination of cotinine and nicotine in biological fluids
Authors: Feyerabend C , Russell M A H
Published: April 2011

A rapid method is described for the simultaneous measurement of nicotine and cotinine in biological fluids using capillary column gas-liquid chromatography. Using 100 μL sample volume the lower limit of detection for both nicotine and cotinine was 100 pg mL−1, allowing the method to be used for the measurement of these compounds in both smokers and non-smokers. The extraction time is 3 min per sample, and by using multi-pipetting and vortexing systems 250 samples can be extracted per day. The average coefficient of variation over the nicotine range 10 to 100 ng mL−1 was 3.9% and for cotinine over the range 1.0 to 1000 ng mL−1 was 2.2%. Saliva cotinine concentrations were quantitatively related to passive exposure to parental smoking in a population study of 1118 non-smoking schoolchildren.
Pre- and Post-junctional α-Adrenoceptor-mediated Responses in the Rat Gastric Fundus In-vitro
Authors: MacDonald A , Kelly J , Dettmar P W
Published: April 2011

The effects of α1-and α2-adrenoceptor agonists on smooth muscle tone and on cholinergic excitatory and non-adrenergic, non-cholinergic inhibitory responses to field stimulation have been investigated in the rat gastric fundus in-vitro. None of the α-adrenoceptor agonists tested, noradrenaline, phenylephrine, cirazoline, guanoxabenz or UK-14,304 showed any contractile effects at concentrations up to 30 μM. In preparations where tone was raised by barium (0.5-2 mM), the mixed α1-and α2-adrenoceptor agonist noradrenaline (0.01–10 μM), and the selective α1-adrenoceptor agonists cirazoline (0.01–10 μM) and phenylephrine (0.01–10 μM) produced concentration-dependent relaxations which were antagonized by the α1-adrenoceptor antagonist prazosin (0.01-1.0 μM). The selective α2-adrenoceptor agonists UK-14,304 (0.03–30 μM) and guanoxabenz (0.03–30 μM), had no relaxant effects in raised tone. UK-14,304 (0.03-1.0 μM) produced a concentration-dependent inhibition of cholinergic nerve-induced responses which was antagonized by the α2-adrenoceptor antagonist idazoxan (0.03-1.0 μM) but not by prazosin (0.03-1.0 μM). Noradrenaline (0.03-1.0 μM) also produced an inhibition of cholinergic nerve-induced responses which was antagonized by idazoxan (0.03–10 μM). A small component of the noradrenaline inhibitory effects was antagonized by prazosin (10%). Cirazoline (0.03-1.0 μM) produced a small inhibition of cholinergic nerve-induced responses which was antagonized by prazosin (0.03-1.0 μM). The prazosin-sensitive components of the inhibitory effects of noradrenaline and cirazoline occurred at concentrations which also produced post-junctional relaxation. UK-14,304 (0.03-1.0 μM) also attenuated non-adrenergic, non-cholinergic (NANC) inhibitory nerve-induced responses and this effect was antagonized by idazoxan (0.03-1.0 μM). The effects of α1-adrenoceptor agonists on NANC nerve-induced responses proved difficult to assess since these agonists caused post-junctional relaxation which itself reduced the size of the inhibitory nerve-induced responses. It is concluded that α-adrenoceptor mediated responses in the rat gastric fundus in-vitro consist of post-junctional α1-adrenoceptor-mediated relaxation of the smooth muscle and pre-junctional α2-adrenoceptor-mediated inhibition of both cholinergic excitatory and non-adrenergic, non-cholinergic inhibitory nerve-induced responses.
Impairment of Endothelium-dependent Relaxation and Changes in Levels of cyclic GMP in Carotid Arteries from Stroke-prone Spontaneously Hypertensive Rats
Authors: Miyata Noriyuki , Tsuchida Katsuharu , Tanaka Makoto , Otomo Susumu
Published: April 2011

Endothelium-dependent relaxation of carotid arteries and changes in levels of cyclic (c)GMP between stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats have been compared. The concentration-response curve for acetylcholine (ACh)-induced relaxation was shifted to the right in carotid arteries from SHRSP. Relaxation responses produced by calcimycin (A 23187) and melittin, both endothelium-dependent agents, were depressed in carotid arteries from SHRSP. Relaxation responses produced by sodium nitroprusside and 8-Br-cGMP were similar to those in strips from WKY. ACh-induced production of cGMP was significantly decreased in carotid arteries from SHRSP when compared with the level for similarly treated strips from WKY. These results suggest that functional changes in endothelium, but not guanylate cyclase activity or cGMP sensitivity in the carotid arteries, may occur in hypertension. Thus, impaired endothelium-dependent relaxation in SHRSP may play an important role in hypertensive vascular diseases such as stroke.
Anti-allergic Effect of N-Acetylneuraminic Acid in Guinea-pigs
Authors: Kai Hirofumi , Murata Yoshiyuki , Ishii Takayuki , Nishijima Sachiko , Murahara Koichiro , Ogasawara Sadanori , Sugiyama Naokazu , Takahama Kazuo , Miyata Takeshi
Published: April 2011

The in-vivo anti-allergic effect of N-acetylneuraminic acid (NANA) in guinea-pigs passively sensitized with anti-ovalbumin rabbit serum has been studied. NANA (20 mg kg−1 i.v.) inhibited bronchial anaphylaxis and the release of histamine into bronchoalveolar lavage fluid. NANA dose-dependently inhibited heterologous passive cutaneous anaphylaxis and haemorrhaging in the passive Arthus reaction. However, it did not inhibit the release of histamine from sensitized minced lung tissue.
Cut-off Effect in Antimicrobial Activity and in Membrane Perturbation Efficiency of the Homologous Series of N,N-Dimethylalkylamine Oxides
Authors: Devínsky Ferdinand , Kopecka-Leitmanová Anna , Šeršeň František , Balgavý Pavol
Published: April 2011

The antimicrobial activity of the homologous series of N,N-dimethylalkylamine oxides (DMAO) was found to be quasi parabolically dependent on alkyl chain length with a maximum at n ∼ 15 and n ∼ 12 for Staphylococcus aureus and Escherichia coli, respectively. The physicochemical properties of DMAOs as characterized by critical micelle concentrations, retention times of 1-alkenes generated from DMAOs by gas-liquid chromatography, Rm values in reversed phase chromatography, and bacterial lipid/aqueous phase partition coefficients were found to correlate with the alkyl chain length. The effect of DMAOs on the structure of the model membrane prepared from isolated lipids from Escherichia coli as detected by a spin probe method was maximal for the alkyl chain length n ∼ 10–12 coinciding with the maximum in the antimicrobial activity observed with Escherichia coli. It is suggested that the cut-off in the DMAO antimicrobial activity is caused by the cut-off in the DMAO perturbing effect on the membrane structure.
Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine
Authors: Brown George R , Forster Gillian , Foubister Alan J , Stribling Donald
Published: April 2011

The synthesis of 2-benzylmorpholine from allylbenzene together with its resolution into its (+)-and (—)-enantiomers is reported. Oral dosing of the racemate to dogs caused appetite suppression with an ED50 of 3 and 5.5 rag kg−1 at I and 2 h, respectively, after access to a meat meal. No stimulant activity was observed in dogs given oral doses of 200 mg kg−1 but the appetite suppressant effect in dogs declined during 20 days of chronic oral dosing at 10 mg kg−1. Appetite suppression activity was shown to reside in the (+)-enantiomer.
The effect of cigarette smoke on the plasma piroxicam concentrations in rats
Authors: Lermioǧlu Ferzan , Berkan Tayfun , Yasa Mukadder , Kerry Zeliha , Yalçinkaya Cengiz , özer Asli
Published: April 2011

The plasma concentration of unchanged piroxicam has been determined at 15, 30, 60 and 90 min after 10 mg kg−1 oral administration of the drug to rats exposed to cigarette smoke or pretreated with phenobarbitone, 3,4-benzpyrene or ethanol. Plasma piroxicam concentrations decreased in rats pretreated with phenobarbitone, 3,4-benzpyrene and ethanol and in rats 24 h after exposure to cigarette smoke.
The binding of physostigmine to human serum albumin
Authors: Whelpton Robin , Hurst Peter R
Published: April 2011

The binding of [3H]physostigmine to crystallized human serum albumin (HSA) has been investigated using equilibrium dialysis. The percentage bound to 1% (w/v) HSA decreased from 18 to 4% as the total concentration of physostigmine increased from 3.3 nM to 2.7 μM (0.9 to 750 ng mL−1). A single class of specific binding sites with a large affinity constant, K = 8 × 107 L mol−1, was identified. The concentration of binding sites was approximately 3 nM. The Michaelis constants for human serum cholinesterase and albumin were the same; an explanation for these results is that the drug is binding to a trace cholinesterase, in the albumin.
Plasma protein binding of disulfiram and its metabolite diethylthiocarbamic acid methyl ester
Authors: Johansson Benny
Published: April 2011

The human plasma protein binding of disulfiram and its metabolite, diethylthiocarbamic acid methyl ester has been studied by an ultrafiltration technique. Both compounds were bound principally to albumin (mean 96.1 and 79.5%) over the ranges 200–800 and 345–2756 nM, respectively. The average number of binding sites was approximately 1 for both substances, whereas the average association constants were 7.1 × 104 and 6.1 × 103 M−1, respectively. Log P (octanol/water) was 2.81 for disulfiram and 1.85 for diethylthiocarbamic acid methyl ester.
Influence of the method of Fluosol-DA administration on antipyrine metabolism in the rat
Authors: Shrewsbury Robert P , White Lisa G
Published: April 2011

Antipyrine disposition has been determined in the rat following administration of Fluosol-DA by an intravenous infusion without blood removal or a haemodilution procedure, and compared with data from sham haemodiluted rats (blood removed and returned) and control rats which only received antipyrine. Antipyrine total body and renal clearance and the formation clearance of two of its metabolites were affected differently at 48 h by the pretreatments. The haemodilution procedure enhanced, the sham haemodilution reduced, and the intravenous infusion had no effect on the phenobarbitone inducible cytochrome P450 isoenzyme activity.
Effects of Solvents and Detergents on the Contractions of Isolated Smooth Muscle Preparations
Authors: Braak Klaus , Frey Hans-Hasso
Published: April 2011

In testing poorly soluble substances in-vitro on isolated organs, organic solvents and solubilizers are used to increase water-solubility. To facilitate selection of appropriate substances, the effects of eleven of these chemicals have been studied in the following isolated smooth muscle preparations: guinea-pig ileum stimulated by carbachol, histamine, 5-HT or single field stimuli; rat fundus stimulated by 5-HT; and mouse vas deferens stimulated by noradrenaline or trains of field stimuli. Nine solvents (acetone, diethyleneglycol monoethylether, dimethyl sulphoxide, ethanol, glycerol, methanol, polyethylene glycol 400, 1,2-propanediol, Tetraglycol (tetrahydrofurfurylalcohol polyethyleneglycolether)) and two detergents (Triton-X 100 and Tween 80) were examined. The vas deferens proved to be most resistent, whereas rat fundus and guinea-pig ileum were more sensitive to the effects of solvent when present from 1 to 10 g L−1. Most solvents caused non-specific, concentration-dependent reversible inhibition of contractions. Dimethyl sulphoxide in high concentrations increased the contractile responses of guinea-pig ileum stimulated by 5-HT and in both experiments with electrical stimulation. Polyethylene glycol 400 augmented the response of mouse vas deferens to electrical stimulation. Overall, 1,2-propylene glycol and polyethylene glycol 400 had the least effect and can be used in a concentration of 3 g L−1, and in qualitative studies even up to 10 g L−1. Glycerol, both monohydric alcohols and dimethyl sulphoxide produced more intense effects and should not exceed concentrations of 1–3 g L−1. Stronger inhibition was caused by diethyleneglycol monoethylether, acetone and Tetraglycol, and the bath concentrations of these substances should not exceed 0.5-lg L−1. Of the detergents only Tween 80 is suitable as a solubilizer in smooth muscle preparations in-vitro, forming micelles at 10 mg L−1 a concentration tolerated by isolated organs in this study.
Enantioselective Structure-pharmacokinetic Relationships of Ring Substituted Warfarin Analogues in the Rat
Authors: Baars L G M , Schepers M T , Hermans J J R , Dahlmans H J J , Thijssen H H W
Published: April 2011

The enantiomer specific pharmacokinetics of ring substituted warfarin analogues have been studied in the rat after the administration of 2 mg kg−1 of the racemates. The stereoselective differences observed were due to stereoselective plasma protein binding and stereoselective intrinsic hepatic clearance. Greater binding was observed for the S-enantiomers except for 2′-substituted analogues where the R-enantiomers were more tightly bound. The stereoselectivity in the binding ranged up to a factor of about 4. All substituted warfarins showed a higher intrinsic clearance than warfarin. Enantiomer selectivity depended on the position of the substituent; warfarin and 3′-substituted analogues showed R > S; 4′-and 2′ substituted warfarins showed S > R stereoselectivity. Exceptions to this generality were seen for 4′-methoxy-and 4′-methylwarfarin which did not show stereoselective hepatic clearance.
Specific binding and clearance of [3H]dynorphin (1–13) in the perfused rat lung: an application of the multiple-indicator dilution method
Authors: Sato Hitoshi , Terasaki Tetsuya , Tsuji Akira
Published: April 2011

The clearance and binding of a κ-selective opioid peptide, dynorphin (1–13), in the perfused rat lung has been examined, using the multiple indicator dilution method. More than 50% of [3H]dynorphin (1–13) entering the pulmonary circulation was eliminated by the lung during a single passage of a tracer dose. By contrast, when a high dose (100 μM) of dynorphin (1–13) was concomitantly injected, [3H]dynorphin (1–13) behaved like [14C]sucrose, an extracellular marker. The kinetic analyses of the pulmonary venous outflow curves of [3H]dynorphin (1–13) and [14C]sucrose at low and high doses of dynorphin (1–13) indicated that the initial uptake rate constant, extraction ratio and distribution volume of [3H]dynorphin (1–13) decreased significantly in the presence of a high concentration of unlabelled dynorphin (1–13). These results suggest that [3H]dynorphin (1–13) is eliminated by a saturable process and binds to a specific binding site in the perfused lung, which may be the κ-type binding site. The multiple indicator dilution technique, in combination with a moment analysis, was successfully applied to demonstrate the specific binding and clearance of dynorphin (1–13) in the perfused lung.
Tissue Distribution of Amphotericin B Lipid Complex in Laboratory Animals
Authors: Olsen Steven J , Swerdel Mavis R , Blue Barbara , Clark Junius M , Bonner Daniel P
Published: April 2011

Amphotericin B lipid complex (ABLC), under development for the treatment of serious fungal disease, is not a true liposome but a complex of amphotericin B, dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol with a particle size range of 1·6–6·0 μm. Tissue distribution of ABLC was determined in mice and rats after i.v. or i.p. administration. ABLC resembles typical liposomal preparations with amphotericin B concentrating in the reticuloendothelial system. After a single i.v. treatment with ABLC, amphotericin B was present in high concentrations in liver, lung and spleen of mice and rats while plasma levels were consistently low. Mouse liver contained 48% of the administered dose 1 h after treatment and always contained the largest amount of amphotericin B after ABLC treatment. In mice treated once daily for 7 consecutive days with 10 mg kg−1 ABLC, liver amphotericin B concentration reached 377 μg g−1. Tissue concentrations of amphotericin B were substantially lower when ABLC was given i.p. instead of i.v. with reticuloendothelial tissues containing 2- to 7-fold more after i.v. treatment. Animals treated with 10 mg kg−1 ABLC for 14 consecutive days showed no overt signs of toxicity and had only transient changes in liver and kidney function after treatment.
In-vitro Skin Pharmacokinetics of Acitretin: Percutaneous Absorption Studies in Intact and Modified Skin from Three Different Species using Different Receptor Solutions
Authors: Surber Christian , Wilhelm Klaus-P , Maibach Howard I
Published: April 2011

The aromatic synthetic retinoid acid derivative, acitretin, is efficacious in several cutaneous diseases. Its toxicological profile makes a topical form with no or reduced systemic adverse effects desirable. Direct application of a topical acitretin formulation might result in therapeutic skin concentrations at the site of the disease while minimizing systemic exposure. The present studies define the percutaneous absorption characteristics of acitretin from an isopropylmyristate formulation. We investigated, in-vitro, (1) the role of receptor solution variations, (2) the role of skin modifications, (3) the influence of skin from three different species on the absorption of topically applied acitretin and (4) the drug distribution within the skin. Addition of solubilizers (Polyethylenglycol-20 and albumin) to the receptor solutions improved the flux of acitretin through monkey skin, whereas the acitretin concentration in the skin was not affected by the various receptor solutions used. Acitretin flux through tape-stripped monkey skin and dermis was only slightly higher than through intact skin. Acitretin concentration in human skin was significantly higher than in rhesus monkey or guinea-pig skin. Topical application of acitretin can produce dermal concentrations in excess of those achieved by therapeutic oral doses.
Ambroxol Inhibits Na+ Absorption by Canine Airway Epithelial Cells in Culture
Authors: Tamaoki Jun , Chiyotani Atsushi , Yamauchi Fumiko , Takeuchi Satomi , Takizawa Takao
Published: April 2011

To study the effect of ambroxol on ion transport functions of airway mucosa, we measured bioelectric properties of canine cultured tracheal epithelium under short-circuit conditions in-vitro. Addition of ambroxol to the submucosal but not to the mucosal solution in an Ussing chamber decreased short-circuit current, transepithelial potential difference and cell conductance. The ambroxol-induced decrease in short-circuit current was not affected by bumetanide or diphenylamine-2-carboxylate, but it was abolished by pretreatment of cells with amiloride. These results suggest that ambroxol may selectively inhibit Na+ absorption by airway epithelium, thereby increasing water composition in airway surface fluid and reducing mucus viscosity.
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G-Nitro-l-arginine methyl ester attenuates vasodilator responses to acetylcholine but enhances those to sodium nitroprusside
Authors: Ralevic Vera , Mathie Robert T , Alexander Barry , Burnstock Geoffrey
Published: April 2011

The effects of NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of the synthesis of the endothelium-derived relaxing factor nitric oxide, were studied in two isolated perfused vascular beds: the rat mesenteric arterial bed and the hepatic arterial bed of the rabbit liver. The tone of both preparations was raised with noradrenaline (10 and 30 μm for rabbit and rat preparations, respectively). In both preparations, L-NAME (30 μm) significantly attenuated vasodilator responses to the endothelium-dependent vasodilator acetylcholine, but enhanced responses to sodium nitroprusside (a direct smooth muscle dilator). The evidence supports the view, previously established from work carried out in isolated vessels, that in addition to acting as an inhibitor of nitric oxide, l-NAME enhances the responsiveness of smooth muscle to direct relaxation by nitrovasodilators.