bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory action of calcitonin gene-related peptide (CGRP) in the mouse colon
Authors: Cadieux Alain , Pomerleau François , St-Pierre Serge , Fournier Alain
Published: April 2011

The effect and mechanism of action of calcitonin gene- related peptide (CGRP) have been investigated on the mouse distal colon. CGRP caused a concentration-dependent relaxation which was not blocked by classical pharmacological antagonists. The response pattern was characterized by a relatively rapid onset and long sustained duration. The results suggest that CGRP itself may contribute to regulating the muscular tone of the mouse colon.
Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats
Authors: Erman A , Chen-Gal B , Zabludowski J , Rosenfeld J B
Published: April 2011

Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg−1 day−1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 ± 9 vs 391 ± 7 nmol mL−1 min−1, P < 0.001; 184 ± 8 vs 142 ± 10 nmol mg−1 min−1  P < 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 ± 0.02 vs 0.51 ± 0.02 nmol mg−1 min−1, P < 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg−1 day−1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg−1 day−1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced. This increased activity may support the suggestion that CSA induces hypertension through an angiotensin II-dependent mechanism and/or an increased degradation of vasodilatory kinins.
The Effect of Solubilized Water on the Size and Shape of Lecithin Micelles in an Apolar Solvent
Authors: Evans Richard M , Attwood David , Chatham Sarah M , Farr Stephen J
Published: April 2011

The changes in the size and shape of the micelles of soya lecithin in trichlorotrifluoroethane following the solubilization of increasing quantities of water have been examined by dynamic and static light scattering and viscometric techniques. Micelles in systems with water/lecithin molar ratios, R, of less than 2.6 were oblate and exhibited no significant changes in asymmetry or aggregation number with changes in the amount of solubilized water. Spherical micelles were evident in systems with R = 2.6 whereas prolate micelles were present in solutions of higher water content (3.5 ≤ R ≤ 5.2). An increase of R in these systems caused a decrease in the axial ratio and an increase in the aggregation number of the micelle.
Moisture Adsorption-desorption Effect on the Structure of Inclusion Complex of 6-Chloro-2-pyridylmethyl Nitrate and β-Cyclodextrin
Authors: Kitamura Satoshi , Koda Shigetaka , Yasuda Tsutomu
Published: April 2011

A new anti-anginal drug, 6-chloro-2-pyridylmethyl nitrate (FR46171), was found to form a complex with β-cyclodextrin (β-CyD), molecular ratio 1:1. The FR46171/β-CyD complex thus prepared showed a moisture adsorption-desorption hysteresis characteristic of hydrophilic polymers. The moisture adsorption-desorption isotherm and differential scanning calorimetry indicated that the moisture adsorbed FR46171/β-CyD complex includes 13–15 mol of water while the moisture desorbed complex includes 5 mol of water. X-ray diffraction patterns of these samples confirmed their different structures. The scanning electron photomicrographs and the surface areas (BET) suggested that the moisture adsorption-desorption hysteresis observed in FR46171/β-CyD complex can be attributed to reversible hydrogen bonding between water molecules and hydroxyl groups.
Rapidly Absorbed Solid Oral Formulations of Ibuprofen Using Water-soluble Gelatin
Authors: Imai Teruko , Kimura Susumu , Iijima Takeo , Miyoshi Tetsu , Ueno Masao , Otagiri Masaki
Published: April 2011

Rapidly absorbed oral dosage forms of ibuprofen using water-soluble gelatin (hydrolysate of common gelatin: mean mol. wt: 6000) have been studied and compared with tablets prepared with common gelatin (mean mol. wt: 100 000) and commercial tablets. Spray-dried and speed-kneaded powders, two types of granules and tablets were prepared with water-soluble gelatin. The in-vitro dissolution rates of water-soluble gelatin preparations were significantly faster than those of commercial tablets, whereas the tablets prepared using common gelatin had slower dissolution rates than commercial tablets. Water-soluble gelatin enhanced the dissolution rate of ibuprofen by improving the wettability of the drug particle surface by water, without any interaction in solution and the solid state. The absorption behaviour of various preparations was evaluated in four beagle dogs. The peak concentration time (tmax) of the water-soluble gelatin preparations was significantly shorter than that of tablets prepared with common gelatin and commercial tablets. The maximum concentration (cmax) and the area under the serum concentration-time curve (AUC0–10 h) were similar in all cases. The serum concentration profiles of water-soluble gelatin solid preparations were almost the same as those of the solutions. On the other hand, the profiles of the common gelatin tablets were similar to those of the commercial tablets. The mean absorption time (MAT) from water-soluble gelatin preparations was about 0.7 h, while the MAT from commercial tablets and common gelatin tablets was about 1.2 h. The differences in the MAT of water-soluble gelatin preparations and commercial tablets or common gelatin tablets were the same as the differences in mean dissolution time (MDT) in gastrointestinal fluid. The MDTs of the water-soluble gelatin preparations were from 1 to 5 min, so both disintegration and dissolution steps were rapid. The water-soluble gelatin preparations were stable at 40°C and 70% RH for at least 30 days. The results suggest that the water-soluble gelatin is a useful additive to solid ibuprofen formulations as it may initiate a more rapid and uniform dissolution and absorption of the drug.
Microcalorimetric Study for the Binding of Ionic Drugs to Human Erythrocytes and the Ghost Membranes
Authors: Aki Hatsumi , Yamamoto Magobei
Published: April 2011

The binding of phenothiazine derivatives (as cationic drugs) and non-steroidal anti-inflammatory drugs (as anionic drugs) to human erythrocytes and ghost membranes has been compared with respect to their thermodynamic characteristics, by flow microcalorimetry at pH 7.4 and 37°C. From enthalpy-entropy correlation, it was shown that anionic and cationic drugs are bound to different binding sites on the membranes. Phenothiazines bind to a single common site of the erythrocyte membranes with relatively high binding affinities (K = 104-105 M−1). The binding is entropy-driven and characterized by a small negative enthalpy (ΔH) and a positive entropy change (ΔS), reflecting hydrophobic interactions. However, the binding reaction for the intact erythrocytes shows large negative values for both AH and AS. The values of K for the membranes and ΔH for the intact erythrocytes increased with the increase of the hydrophobic character of the substituent group at the C-2 position of the phenothiazine nucleus (H < Cl < CF3). The results indicate that phenothiazines bind and/or penetrate to the inner membranes of the erythrocytes and react with intracellular components such as haemoglobin, while anti-inflammatory drugs bind to the surface protein on the membranes with a lower affinity (K = 103 M−1) than phenothiazines, reflecting the small negative ΔH and positive ΔS for the interaction with intact erythrocytes.
Cerebral Pharmacokinetics of Ipsapirone in Rats After Different Routes of Administration
Authors: Nocon H , Daniel W , Danek L , Melzacka M
Published: April 2011

Ipsapirone, a putative non-benzodiazepine anxiolytic, was extensively metabolized in rats to 1-(2-pyrimidinyl)piperazine (1-PP) which accumulated in the brain. Neither the route of administration (i.p. or p.o.), nor prolonged administration of ipsapirone or 1-PP affected their accumulation in the rat brain. The cytochrome P450 level and ethylmorphine N-demethylase activity in rat liver microsomes were unchanged by chronic treatment with ipsapirone or 1-PP. The results indicate that 1-PP may contribute to the α2-adrenoceptor antagonism of ipsapirone in rats and that chronic treatment with the drug does not affect its biotransformation to 1-PP.
Potent inhibition of prostaglandin inactivation in rabbit gastric antral mucosal slices by selenium ions in-vitro
Authors: Fujita Tadashi , Nakatani Emi , Funaishi Nobuyuki , Sakuma Satoru , Fujimoto Yohko
Published: April 2011

The effect of selenium ions on prostaglandin (PG) catabolism and synthesis in rabbit gastric antral mucosal slices has been examined. Selenium ions had a potent inhibitory effect on the inactivation process for PGE2 and PGF2α. Simultaneously, the levels of PGE2 and PGF2α were increased. These results suggest that selenium ions have the potential to increase the levels of biologically active PGs in gastric mucosa by preventing their inactivation and that this effect may represent some pharmacological action of selenium ions.
Cortisone: a potent GABAA antagonist in the guinea-pig isolated ileum
Authors: Ong Jennifer , Kerr David I B , Capper Hugh R , Johnston Graham A R
Published: April 2011

In the guinea-pig isolated ileum, cortisone at 0.001–10 nM induced a non-competitive, dose-dependent antagonism of GABAA-receptor-mediated contractile responses to applied GABA, depressing the maximum contractile response to GABA (100 μM), without affecting contractile responses to acetylcholine or cholinergic twitch contractions. At higher concentrations (>10 nM), cortisone depressed contractile responses to acetylcholine (10–100 nM) and cholinergic twitch responses to transmural stimulation. Cortisone is thus the most potent non-competitive antagonist at GABAA-receptor complexes in the guinea-pig ileum. From molecular modelling, sterically there appeared little difference between cortisone and cortisol, the latter being an enhancer of GABAA-receptor-mediated action in the ileum. However, there were significant differences in electrostatic potentials between the two steroids, due to the different levels of oxidation at C11 which may contribute to such opposing actions.
Enhancement of Morphine Clearance Following Intravenous Administration by Oral Activated Charcoal in Rabbits
Authors: El-Sayed Y M , Hasan M M
Published: April 2011

A single dose of activated charcoal (10 g) significantly reduced the half-life of elimination (1.02 ± 0.10 and 0.70 ± 0.04 h for the control and treated groups, respectively) and mean residence time (1.01 ± 0.12 and 0.76 ± 0.05 h for the control and treated groups, respectively) of morphine in rabbits. A 40% increase in the systemic clearance (85.73 ± 7.72 and 122.64 ± 16.32 mL min−1 kg−1 for the control and treated groups, respectively) and a 30% decrease in AUC (204.38 ± 22.20 and 140.03 ± 19.32 μg h L−1 in the control and treated groups, respectively) were also noted. Charcoal administration did not significantly alter the volume of distribution (Varea and VSS) or the apparent distribution half-life. A two-compartment model adequately described morphine kinetics in control and treated rabbits; charcoal administration produced a significant increase in the tissue compartment rate constant (K21). This finding indicates that activated charcoal not only enhances the systemic elimination of morphine, but also accelerates the rate of transfer of morphine from the tissue compartment to the central compartment.
Prostaglandin E2-mediated Stimulation of Mucus Synthesis and Secretion by Rhein Anthrone, the Active Metabolite of Sennosides A and B, in the Mouse Colon
Authors: Yagi Teruyo , Miyawaki Yoshie , Nishikawa Atsuko , Horiyama Shizuyo , Yamauchi Kazuko , Kuwano Shigeaki
Published: April 2011

Rhein anthrone, the active metabolite of sennosides A and B, stimulated PGE2 release into the mouse colonic lumen. At 6.24 mg kg−1, it decreased net water and Na+ absorption significantly in the case of water, but could not reverse the net absorption in mouse ligated colon, although it enhanced net K+ secretion. Pretreatment with indomethacin diminished the effects of rhein anthrone except on K+ net secretion. Rhein anthrone or PGE2 markedly stimulated mucus secretion and synthesis in mouse ligated colon. The enhanced mucus secretion and synthesis induced by rhein anthrone were significantly suppressed by pretreatment with indomethacin. Our results have shown that the colonic secretion of water and electrolytes mediated by PGE2 is partly involved in the rhein anthrone-induced diarrhoea but that in mice, the mucoid diarrhoea induced by rhein anthrone results mainly from PGE2-mediated mucus synthesis and secretion in the colon.
A Comparison of the Effects of an Extract of Feverfew and Parthenolide, a Component of Feverfew, on Human Platelet Activity In-vitro
Authors: Groenewegen W A , Heptinstall S
Published: April 2011

Extracts of the herb feverfew inhibit human blood platelet aggregation and secretion induced by a number of agents in-vitro and this may relate to the beneficial effects of feverfew in migraine. We previously identified several compounds with antisecretory activity in human blood platelets using adrenaline as the stimulant. In the present study, we have compared the inhibitory activity of one of these compounds, parthenolide, with that of crude feverfew extract. The effects of both on [14C]5-HT secretion from platelets and on platelet aggregation induced by a number of different stimulants were determined. The activating agents studied included the phorbol ester PMA, ADP, arachidonic acid, collagen, the thromboxane mimetic U46619, the calcium ionophore A23187, the diacylglycerol analogue OAG and adrenaline. The results show that there are marked similarities between the effects of feverfew extract and of parthenolide on both [14C]5-HT secretion and platelet aggregation, which is consistent with the effects of feverfew extract on platelets being brought about by parthenolide or similar compounds in the extract. Only in one case, when A23187 was used as the stimulatory agent, was there any discrepancy, which may have been due to materials in the extract other than parthenolide. Both feverfew extract and parthenolide were more effective as inhibitors of the [14C]5-HT secretion and aggregation induced by some agents and not others, and were most effective as inhibitors of the [14C]5-HT secretion (but not the aggregation) induced by PMA. This suggests that the effects of feverfew/parthenolide on the protein kinase C pathway warrants further study.
Effect on Cerebral Blood Flow of Orally Administered Indomethacin-loaded Poly(isobutylcyanoacrylate) and Poly(DL-lactide) Nanocapsules
Authors: Ammoury Nazih , Fessi Hatem , Devissaguet Jean-Philippe , Allix Monique , Plotkine Michel , Boulu Roger G
Published: April 2011

Nanocapsules, containing indomethacin, were prepared either by interfacial polymerization of isobutylcyanoacrylate monomers or by interfacial deposition of a preformed (DL-lactide) polymer. In-vitro release of indomethacin from nanocapsules was dependent on the pH of the sink solution and was enhanced by addition of albumin. A decrease in cerebral blood flow was noted 15 min after oral administration to rats of indomethacin nanocapsules (5 mg kg−1) and lasted over 3 h. Empty nanocapsules had no effect. Since release of indomethacin from nanocapsules is unlikely to occur in the lumen of the stomach, due to unsuitable pH conditions, and nanocapsules have been previously shown to be able to cross the intestinal barrier, to reach the villi vessels intact and to protect against the ulcerating effect of the free drug, it is suggested that the rapid onset of the pharmacological effect was sufficiently induced by free indomethacin released in the plasma following absorption of the intact nanocapsules.
Preferential Decrease in Dopamine Utilization in Prefrontal Cortex by Zopiclone, Diazepam and Zolpidem in Unstressed Rats
Authors: Boireau A , Dubedat P , Laduron P M , Doble A , Blanchard J C
Published: April 2011

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg−1 p.o.) and diazepam (10 and 40 mg kg−1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg−1 p.o.). Diazepam (10 and 40 mg kg−1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg−1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15–1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor/GABA receptor/chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.
The Effects of Haematocrit, Plasma Protein Concentration and Temperature of Drug-containing Blood In-vitro on the Concentrations of the Drug in the Plasma
Authors: Tamura Akira , Sugimoto Kazumoto , Sato Takashi , Fujii Tatsuzo
Published: April 2011

Factors which influence the plasma drug concentrations in whole blood have been investigated in-vitro using human blood containing radio-labelled phenytoin or chlorpromazine. Phenytoin (3.55 μg mL−1, 0.01 mM) or chlorpromazine (2.74 μg mL−1, 0.01 mM) was mixed with normal or modified blood and the plasma drug level was measured. Plasma phenytoin and chlorpromazine levels decreased with decrease in the protein concentration of plasma, but were not influenced by addition of y-globulin to the blood specimen. Plasma phenytoin levels increased with an increase in haematocrit from 20 to 45%, whereas the chlorpromazine level remained constant. The partition coefficients of phenytoin and chlorpromazine between blood cells and plasma were almost the same at various haematocrit values. By cooling the blood containing each drug to 4°C, plasma phenytoin and chlorpromazine levels were higher compared with those at 37°C. Similar temperature effects on the drug levels in plasma were obtained when the washed erythrocytes were resuspended in albumin medium, but not when resuspended in saline.
Effect of structural variations of non-ionic surfactants on surface properties: surfactants with semi-polar hydrophobes
Authors: Attwood D , Elworthy P H , Lawrence M J
Published: April 2011

The surface properties of a series of non-ionic surfactants in which a polar group (either an ether or a keto group) has been introduced into a hydrocarbon chain of octadecylpolyoxyethylene glycol monoether (C18E17–19) have been investigated. Surface tension measurements indicated that the critical micelle concentrations for these semi-polar surfactants in aqueous solution were all significantly higher than those of C18E22, the corresponding unsubstituted octadecylpolyoxyethylene glycol monoether. The minimum areas per molecule of the semi-polar surfactants in the surface monolayer were all larger than the area obtained for C18E22, from which it was concluded that the hydrophobe, and not the polyoxyethylene chain was the main determinant of surface area.
Differential scanning calorimetry characterization of process-induced variations in an ointment base
Authors: Timmins Peter , Browning Ivan , Payne Nicholas I
Published: April 2011

Preparation of an experimental emollient wax-gelled ointment base by two processes differing only in cooling rate produced material with markedly different physical properties. Differential scanning calorimetry showed that a major endotherm, possibly related to a phase change in a major triglyceride wax component, Synchrowax HGLC, was different in the two products. Mean enthalpies for this major endotherm for the two products were 7.36 J g−1 (s.d. = 0.49, n = 5) in slow cooled samples and 4.35 J g−1 (s.d. = 0.21, n = 5) in fast cooled samples. The degree of order of the Synchrowax HGLC in the ointment is suggested as being different in the two preparations and it is this that controls the physical properties of the ointment.
In-vitro antibacterial activity of noxythiolin and taurolidine
Authors: Blenkharn J Ian
Published: April 2011

The minimum inhibitory concentrations (MIC) of noxythiolin and taurolidine were determined for strains of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Tests were performed in broth alone and in broth plus 25% v/v serum or 25% v/v urine. Inoculum density was either 103, 105 or 107 colony forming units per mL−1. Slight inoculum-dependent variation in the activity of both agents was observed for some, but not all, strains of P. aeruginosa and S. aureus. A more pronounced medium-dependent increase in activity was observed with both drugs, with up to 8-fold reduction of values for MIC when tested in the presence of serum or urine. These observations may help to clarify the disparity between the observed clinical efficacy of these agents and relatively poor in-vitro activity when tested using conventional methods in synthetic media.
Comparative effects of (+)-propranolol and nonoxynol-9 on human sperm motility in-vitro
Authors: Gadd A L , Curtis-Prior P B
Published: April 2011

Using the modified transmembrane migration method to measure sperm motility, it was shown that the surfactant nonoxynol-9 alone, was twice as potent as (+)-propranolol alone as a spermicidal agent. Addition of (+)-propranolol to nonoxynol-9 shifted the dose-response curve to the left of the curves for either component alone, and a surprising synergistic action was evident. These observations may form the basis for the development of a new advantageous topical contraceptive combination product.
The relative dependence of calcium antagonists and neuroleptics binding to brain and heart receptors on drug lipophilicity
Authors: Rojratanakiat Winyu , Hansch Corwin
Published: April 2011

QSAR analysis of the binding of calcium antagonists to brain and heart tissue shows that relative binding to brain tissue increases with increasing octanol/water partition coefficients. A number of antischizophrenic drugs follow the same pattern.
Evaluation of Release from Selected Thermosoftening Vehicles
Authors: Kopcha Michael , Lordi Nicholas G , Tojo Kakuji J
Published: April 2011

Release of D&C Yellow No. 10 and anhydrous theophylline have been determined from a thermosoftening, hydrophilic matrix, Gelucire 50/13, incorporating a water-soluble additive, polyethylene glycol 4000. As additive level increased, release also increased. The effect of mixtures of Gelucire 50/13 (G50/13) and Gelucire 50/02 (G50/02) on release was also investigated as a function of temperature and pH. As the level of G50/02 increased, release decreased and became predominantly diffusional. As temperature was increased, release changed from diffusion to a mixed model of both diffusion and erosion. At basic pH, release from these composite systems became more erosional in character, possibly reflecting partial hydrolysis of the ester-linked matrices. Diffusion coefficients and apparent diffusion coefficients were calculated in G50/02 and G50/13 matrices, respectively, and were in agreement with published data.
Epithelium Modulates the Reactivity of Sensitized Guinea-pig Trachea: Influence of the Surface of Drug Entry
Authors: Iriarte C F , Pascual R , Villanueva M M , Román M , Ortiz J L , Cortijo J , Morcillo E
Published: April 2011

A technique by which drug access was restricted to either the mucosal or the adventitial surface of tracheal rings isolated from sensitized guinea-pigs was applied to study the role of the epithelium in modulating responses to KCl, acetylcholine, histamine and antigen (bovine serum albumin, BSA). Epithelium removal did not alter the responsiveness or sensitivity of tracheal rings to KCl. In contrast, a leftward shift occurred for concentration-response curves to acetylcholine (concentration ratio (CR) = 4·1), histamine (CR = 2·9) and BSA (CR = 33·9) entering from the mucosal surface of de-epithelialized trachea. This shift was not associated with changes in the maximal effect of the spasmogens. Response to the adventitial entry of these spasmogens was not altered by epithelial stripping. These results confirm that the epithelium modulates tracheal responses to certain spasmogens including antigen challenge. This role was exclusively exerted for mucosal drug entry. The mechanism underlying this protective effect of epithelium remains to be determined.
Influence of Calcium Entry Blockers and Calmodulin Inhibitors on 5-Hydroxytryptamine-, Potassium- and Calcium-induced Contractions in Human Umbilical Artery In-vitro
Authors: Medeiros Yara S , Calixto João B
Published: April 2011

The effects of calcium (Ca2+) withdrawal, Ca2+ entry blockers and calmodulin inhibitors on the contractile responses to 5-hydroxytryptamine (5-HT), K+ and CaCl2 have been studied in human isolated umbilical artery. Following Ca2+ withdrawal from the medium (30 min), both 5-HT- and K+ -induced contractions were virtually abolished. Ca2+ entry blockers (nifedipine, verapamil, diltiazem and cinnarizine) were significantly more effective in inhibiting 5-HT- than K+-induced contractions. In relation to calmodulin inhibitors, trifluoperazine inhibited all types of contractions, whereas W-7 (N-6-aminohexyl-5-chloro-1-naphthalene sulphonamide) only inhibited 5-HT- and CaCl2-induced contractions. All drugs inhibited CaCl2-induced contractions in a non-competitive manner. These findings indicate that the mechanisms by which these drugs exert their inhibitory effects on human umbilical artery are markedly different from those reported in other vascular beds.
Blockade by 4-Aminopyridine of the Muscarinic-receptor-mediated Responses of Guinea-pig Atria and Trachea
Authors: Urquhart Robert A , Broadley Kenneth J
Published: April 2011

The potassium channel blocker 4-aminopyridine (4-AP) has been shown to antagonize the negative inotropic effects of muscarinic receptor agonists on atrial preparations. This is consistent with muscarinic agonists mediating their negative inotropy through the opening of potassium channels. In the present study, the possibility of a direct antagonism of the muscarinic receptor was examined by comparing the effects of 4-AP upon the responses to carbachol of isolated left atria (negative inotropy) and tracheal spirals (contraction) from reserpine pretreated guinea-pigs. The latter response is K+ channel-independent. The concentration-response curve for carbachol on the paced left atria was displaced 520-fold to the right by 4-AP (10 Mm). 4-AP alone caused dose-related contractions of the tracheal spirals. Carbachol-induced contractions were, however, superimposed upon the raised tone and there were substantial rightwards shifts of the concentration-response curves of 4·7- and 31·4-fold by 1 and 10 Mm of 4-AP, respectively. Thus 4-AP appears to have muscarinic receptor antagonistic blocking properties. The blockade of the atrial responses was, however, substantially greater and could be attributed to an additional blockade of muscarinic receptor-linked potassium channels. The negative inotropic responses of the A1- adenosine receptor agonist l-phenylisopropyladenosine (l-PIA) were also antagonized by 4-AP, but to a lesser extent than for carbachol. After allowing for the muscarinic receptor blocking activity of 4-AP, carbachol was still antagonized more effectively than L-PIA. This could be due to the presence of a K+ channel-independent component in the response to l-PIA which is not susceptible to 4-AP.
Dopamine Receptor Mediated Hypothermic Action of B-HT 920 in Rats
Authors: Verma A , Kulkarni S K
Published: April 2011

The hypothermic action of the thiazoloazepine derivative B-HT 920, an α2-adrenoceptor agonist has been investigated in rats. B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)-azepine dihydrochloride) (0·25–10 mg kg−1 i.p.) induced a dose-dependent hypothermia. The peak effect was seen within 60·90 min and lasted up to 120 min. Its action was potentiated by the selective D1-dopamine agonist SKF 38393 and inhibited by the D2-anatagonists haloperidol (1 mg kg−1) and sulpiride (100 mg kg−1). The hypothermic action of B-HT 920 was centrally mediated; i.c.v. administration of 10 μg produced a significant fall in rectal temperature which was sensitive to blockade by haloperidol. B-HT 920 also potentiated the hypothermic action of apomorphine (0·1 and 0·5 mg kg−1) in a haloperidol sensitive manner. Reserpine (5 mg kg−1 i.p.) pretreatment reduced the hypothermic response of B-HT 920 (0·5 mg kg−1) but sensitized the response due to the combination of B-HT 920 (0·5 mg kg−1) and apomorphine (0·1 mg kg−1). Neither the selective α2-adrenoceptor antagonists, yohimbine (1 mg kg−1) or idazoxan (1 mg kg−1), the histamine antagonist mepyramine (10 mg kg−1) nor the 5-HT antagonist cyproheptadine (5 mg kg−1) inhibited B-HT 920-induced hypothermia. Similarly, the selective α1-antagonist prazosin (1 mg kg−1) and the β-antagonist propranolol (10 mg kg−1) failed to modify the hypothermic action of B-HT 920. These observations demonstrated hypothermia induced by B-HT 920 is mediated by postsynaptic D2-receptors and D1- and D2-receptor interplay is essential for the full expression of hypothermia in rats.
Enhancement of 4-biphenylacetic acid bioavailability in rats by its β-cyclodextrin complex after oral administration
Authors: Puglisi G , Santagati N A , Ventura C A , Pignatello R , Panico A M , Spampinato S
Published: April 2011

4-Biphenylacetic acid, a potent non-steroidal antiinflammatory agent forms a solid inclusion complex with β-cyclodextrin in a 1:1 molar ratio, which exhibits better solubility and dissolution characteristics than the uncomplexed drug. Following oral administration of the complex to rats, quicker and higher drug plasma concentrations can be achieved than with the drug alone. Parallel studies, using the carrageenan paw oedema test, demonstrate a greater anti-inflammatory activity of the complex (ED50 of 2·9 mg kg−1 for the complex and of 6·2 mg kg−1 for the free drug). The complex displayed a better gastric tolerability in the rat than drug alone.
Effects of calcium channel inhibitors on the hypothermic response to oxotremorine in normo and hypercholinergic rats
Authors: Pucilowski Olgierd , Overstreet David H , Rezvani Amir H , Janowsky David S
Published: April 2011

The Flinders Sensitive Line of rats (FSL) has been selectively bred to have increased sensitivity to cholinergic drugs. Typically, these rats react with twice as great a hypothermic effect to muscarinic agonists such as oxotremorine, as do similarly bred Flinders Resistant Line rats (FRL). We compared the effects of three chemically different calcium channel inhibitors (diltiazem, nicardipine and verapamil) on the hypothermia induced in FRL and FSL rats by oxotremorine (0·2 mg kg−1  s.c). Each drug was injected i.p. in a dose of 20 μmol kg−1 30 min before oxotremorine. Methylatropine (2 mg kg−1  s.c.) was administered 15 min before oxotremorine to block the peripheral effects of the agonist. The hypothermic effect of oxotremorine in FSL rats was antagonized by nicardipine and diltiazem. In contrast, verapamil failed to influence the hypothermic response in FSL rats. Verapamil significantly (P < 0·05) augmented oxotremorine hypothermia in FRL rats. Diltiazem and nicardipine were without effect on oxotremorine-induced hypothermia in FRL rats. There were no significant changes in temperature in separate groups of FRL and FSL rats treated with calcium channel inhibitors alone.
Role of calcium in the analgesic action of tetrahydroisoxazolepyridinol and muscimol
Authors: Aram S Raj , Ramaswamy S , Bapna J S
Published: April 2011

The role of calcium in the analgesic activity of 4,5,6,7-tetrahydroisoxazole-(5,4-c) pyrídin-3-ol (THIP) and muscimol has been investigated using the acetic acid assay procedure. THIP and muscimol produced significant analgesic response. Whilst neither calcium chloride nor nifedipine in the doses employed significantly altered the number of writhings, calcium chloride antagonized the analgesic responses of THIP and muscimol while nifedipine potentiated them. Similar responses were recorded for morphine. These findings suggest that THIP and muscimol, like morphine, might alter the calcium movements across the plasma membrane to elicit the analgesic response.
Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity
Authors: Sakane Toshiyasu , Akizuki Motohiro , Yoshida Masako , Yamashita Shinji , Nadai Tanekazu , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

The aim of the present study has been to confirm the existence of a transport pathway for a drug (cephalexin) to the cerebrospinal fluid (CSF) directly from the nasal cavity, by comparing the drug's concentrations in CSF after intranasal (i.n.), intravenous (i.v.) and intraduodenal (i.d.) administration. Higher levels of the drug were found in CSF following i.n. administration compared with the i.v. and i.d. routes, even though its plasma concentrations were similar. These findings suggest the existence of a direct transport pathway for cephalexin from the nasal cavity to the CSF. The concentration of drug in CSF at 15 min after i.n. administration was higher than that at 30 min. In contrast, its concentrations in CSF at 15 min after i.v. and i.d. administration were not significantly different from those at 30 min. The results confirm the presence of a direct transport pathway to CSF from the nasal cavity. This pathway may represent a new delivery route to CSF and possibly to brain parenchyma.
Formulation Effects on the Mechanical Properties of Metronidazole Tablets
Authors: Itiola O A , Pilpel N
Published: April 2011

The individual and interaction effects of nature of binder (N), concentration of binder (C) and the physical form of the formulation (P) on the tensile strengths (T—a measure of the bond strength of tablets) and the brittle fracture index values (BFI—a measure of the lamination tendency of tablets) of metronidazole tablets have been studied using a 23 factorial experimental design in each case. Changing binder concentration from a ‘low’ to a ‘high’ level increased T and reduced the BFI of the tablets. Methylcellulose 20 exhibited stronger binding effect and greater ability to reduce the lamination tendency of the tablets than polyvinylpyrrolidone of molecular weight 44000. Granular formulations produced tablets with lower T values but also with lower BFI values than tablets produced from powdered formulations. The ranking of these individual effects on tensile strength was P > C > N while the ranking for the BFI was P > N > C. For the interaction effects, the ranking for tensile strength was P—N ≫ N—C > P—C while the ranking for the BFI was N—C ≫ P—C > P—N.
Saturable, Non-Michaelis-Menten Uptake of Liposomes by the Reticuloendothelial System
Authors: Kume Yoshihiro , Maeda Fumiyo , Harashima Hideyoshi , Kiwada Hiroshi
Published: April 2011

Multilamellar vesicles (300–350 nm) were infused into the rat femoral vein at the rate of 4, 40 and 400 nmol phosphatidycholine min−1 for 6 h using [3H]inulin as an aqueous marker. The time courses of blood concentration of vesicles, normalized for infusion rate, were not superimposable, showing the non-linearity of liposome disposition in the blood circulation. These time courses of blood concentration were well fitted by a single Michaelis-Menten equation. On the other hand, the time courses of tissue content could not be so accommodated. Additionally, the observed relationship between the uptake of liposomes by the liver and their clearance from it and other organs differed essentially from a simulation based on Michaelis-Menten type saturable kinetics. Therefore, it is suggested that there is a time-dependent non-Michaelis-Menten type process in the phagocytosis of macrophages in the reticuloendothelial system.
In-vitro Evidence for Carrier-mediated Uptake of Acidic Drugs by Isolated Bovine Brain Capillaries
Authors: Terasaki Tetsuya , Kang Young Sook , Ohnishi Toshimasa , Tsuji Akira
Published: April 2011

[3H]Acetic acid was taken up into the isolated brain capillaries in a temperature and concentration dependent manner. The initial uptake rates were pH dependent over the range 5.0–7.4. An increase of the uptake rate with decrease in medium pH was not seen in the presence of unlabelled acetic acid (10 mM). The uptake of [3H]acetic acid was significantly reduced in the presence of several drugs having a monocarboxylic group. The initial uptake of [14C]salicylic acid was also pH dependent and was inhibited by acetic acid and acidic drugs. A mutually competitive inhibition was observed for the uptake of acetic acid and salicylic acid. The present study demonstrates that acidic drugs having a monocarboxylic group are transported by a common carrier-mediated system into the brain capillaries.
The Use of a Radiolabelled Saccharin Solution to Monitor the Effect of the Preservatives Thiomersal, Benzalkonium Chloride and EDTA on Human Nasal Clearance
Authors: Batts Alison H , Marriott Christopher , Martin Gary P , Bond Steven W , Greaves Jane L , Wilson Clive G
Published: April 2011

The effect of thiomersal, benzalkonium chloride and ethylenediaminetetraacetic acid (EDTA) on the nasal mucociliary clearance of healthy volunteers has been investigated using a modified saccharin test and gamma scintigraphy concomitantly. A significant correlation was found between the two techniques. Using each subject as his/her own control, none of the preservatives significantly altered the rate of clearance or proportion cleared from the nasal cavity after the administration of a single dose. This result is at variance with some in-vitro findings.
Determination of Lipophilicity and Hydrogen-bond Donor Acidity of Bioactive Sulphonyl-containing Compounds by Reversed-phase HPLC and Centrifugal Partition Chromatography and their Application to Structure-activity Relations
Authors: Altomare Cosimo , Tsai Ruey-Shiuan , Tayar Nabil El , Testa Bernard , Carotti Angelo , Cellamare Saverio , De Benedetti Pier G
Published: April 2011

The lipophilic character of two large series of substituted benzenesulphonamides (BzSA) and 4-aminodiphenylsulphones (4-ADS) has been assessed by two chromatographic methods, i.e. reversed-phase HPLC using a relatively novel octadecylpolyvinyl packing and centrifugal counter-current chromatography (CPC). The octadecylpolyvinyl stationary phase proved an interesting alternative to the more common octadecylsilane type stationary phase for obtaining retention parameters correlated to partition coefficients (i.e. log P). The CPC method, being far less time-consuming and markedly more precise than the classical shake-flask method, offers a promising alternative for measuring partition coefficients. The parameter Δlog Poct-hep, i.e. log Poctanol minus log Pheptane, was also determined for both congeneric series and was indicative of a similar H-bonding capacity for the SO2NH2 and 4-NH2-C6H4-SO2 groups. QSAR analyses of carbonic anhydrase inhibition by BzSA and antimycobacterial activity of 4-ADS show the capacity of the new lipophilicity parameters to express the hydrophobic component of the drug-enzyme interactions and to reveal a possible role of H-bond donor capacity in governing the antimycobacterial activity of 4-ADS.
Effect of chronic administration of nicotine or cocaine on steroidogenesis in rat adrenocortical cells
Authors: Krueger Rick J , Lin Chaomei , Fung Yiu K
Published: April 2011

Rats were implanted subcutaneously with osmotic mini-pumps containing either 0.9% NaCl, nicotine (1.5 or 4.5 mg kg−1 day−1), or cocaine (30 mg kg−1 day−1), for 14 days. Neither nicotine nor cocaine treatment significantly altered the maximal rate of steroidogenesis in adrenocortical cell preparations from the animals. However, pretreatment with cocaine increased the sensitivity of the preparation to stimulation by ACTH, the ED50 was 5 pM compared with 10 pM from control animals. Addition of nicotine or cocaine at concentrations up to 100 μM to adrenal cell suspensions from naive rats did not stimulate steroidogenesis or increase the sensitivity of cells to ACTH stimulation. These results suggest that the primary chronic effect of nicotine on steroidogenesis is exerted at the level of the hypothalamus and/or pituitary and not directly on adrenocortical cells. On the contrary, pretreatment with cocaine causes persistent changes in adrenocortical cells.
Influence of lipophilic counter ions on the transport of ionizable hydrophilic drugs
Authors: Neubert Reinhard , Fischer Silke
Published: April 2011

The influence of lipophilic counter ions on the transport of the hydrophilic drugs pholedrine and bretylium across artificial lipid membranes has been studied using a permeation model system. The transport of both drugs was markedly enhanced by hexylsalicylate and by salts of fatty acids with a maximum at decanoate. The transport of pholedrine was additionally increased by bile salts such as desoxycholate.
Differential responses of human and rat cartilage to degrading stimuli in-vitro
Authors: Ismaiel S , Hollander A P , Atkins R M , Elson C J
Published: April 2011

Human cartilage biopsies incubated for 2 days in-vitro with 15% synovial fluid from rheumatoid arthritis patients contained less glycosaminoglycans (GAG) than control biopsies. Recombinant human (rHu-) interleukin-1α (IL-1α) and IL-1β at 10 or 100 ng mL−1 had no effect on human cartilage GAG levels. Similarly, GAG loss from human cartilage biopsies into medium over 5 days was significantly increased by synovial fluid but unaffected by 100 ng mL−1 IL-1α or IL-1β compared with controls. However, when rat femoral head cartilage samples were incubated with 100 ng mL−1 rHu-IL-1α or IL-1β for 5 days there was a significant increase in GAG loss from the cartilage into medium, whilst human synovial fluid significantly decreased the loss of GAG from rat cartilage into medium, compared with controls. The results demonstrate that human and rat cartilage differ from each other in their responses to degrading stimuli and suggest that animal cartilage may have limited application for the screening of drugs intended for the treatment of human arthritides.
Antidiuretic effect of bremazocine and U-50,488 in rats after α2-adrenoceptor blockade
Authors: Bianchi Giancarlo
Published: April 2011

The role of α2-adrenoceptors and κ-opioid receptors in urination was studied in rats. In water-loaded rats (40 mL kg−1 p.o.) the κ-opioid agonist bremazocine (0.05-0.2 mg kg−1 i.p.) induced a dose-related diuretic response in the second hour after administration, but had no effect in the first hour. When rats were pretreated with the α2-adrenoceptor antagonist idazoxan (1 mg kg−1 s.c.), bremazocine induced a dose-related antidiuretic response in the first hour; thereafter the rats showed an increase of urination similar to that with bremazocine alone. The antidiuretic effect of bremazocine was dependent on the dose of idazoxan with maximal response after 1–3 mg kg−1. Similar results were obtained with bremazocine in the presence of yohimbine (1 mg kg−1 s.c). The antidiuretic profile of bremazocine after idazoxan was shared by U-50,488 (2.5–10 mg kg−1 i.p.), although this compound alone at the high dose reduces urine output in the first hour. The antidiuresis induced by bremazocine in the presence of idazoxan in water-loaded rats was completely antagonized by 10 but not 2 mg kg−1 i.p. of the opioid antagonist naloxone. Thus, κ-opioid agonists, in addition to their diuretic effect, also produce an antidiuretic response which may be mediated by α2-adrenoceptors.
Histological Findings in Rabbit Lymph Nodes After Endolymphatic Injection of Liposomes Containing Blue Dye
Authors: Hirnle P
Published: April 2011

Liposomes produced from phosphatidylcholine and cholesterol and containing Patent Blue V have been injected endolymphatically in the rabbit. The lymph nodes stained dark blue and retained this colour until termination of the experiment after 28 days. No toxic effects were observed histologically. The liposomes were deposited within the macrophages in a fine granular pattern. Because endolymphatic injection of such liposomes produces excellent contrast between retroperitoneal lymph nodes and their surrounding fatty tissue, it can improve both the radicality and the selectivity of lymphonodectomy in oncological surgery.
Characterization of Albumin-acacia Complex Coacervation
Authors: Burgess D J , Kwok K K , Megremis P T
Published: April 2011

Complex coacervation between oppositely charged albumin and acacia mixtures has been studied, and the applicability of the various theoretical treatments of complex coacervation (the Voorn-Overbeek, Veis-Aranyi, Nakajima-Sato, and Tainaka theories) to this system has been assessed. Under optimum conditions where maximum coacervate yield occurred, the Voorn-Overbeek theory appeared to apply. However, away from the optimum coacervation conditions, coacervate sol formation was observed, which is in accordance with the Veis-Aranyi and Tainaka theories. Microelectrophoretic measurements were used to determine optimum pH and ionic strength conditions for maximum coacervation, based on the method of Burgess & Carless (1984). The effects of pH and ionic strength on coacervate yield are reported. Around the optimum conditions for maximum coacervation a viscous coacervate phase and a relatively clear equilibrium phase are formed.
Inhibitory Effects of Non-narcotic Antitussive Drugs on Cholinergically and Non-cholinergically Mediated Neurogenic Contractions of Guinea-pig Isolated Bronchial Muscle
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

We have examined the actions of non-narcotic antitussive drugs on the response evoked by electrical field stimulation or by acetylcholine (ACh) and neurokinin A (NKA) on guinea-pig bronchial strip chain. Electrical field stimulation (1–32 Hz, 0.5 ms, 30 V for 5 s) evoked a biphasic contraction in a frequency-dependent manner, consisting of a cholinergically mediated fast contraction followed by a non-cholinergically mediated slow contraction. Dextromethorphan (1–300 μM) and tipepidine (0.1–100 μM) caused a concentration-dependent inhibition in the height of the biphasic contraction, but noscapine (1–300 μM) was less effective. Submaximal contractions of bronchial muscle evoked by exogenous ACh (1–30 μM) were inhibited by tipepidine (10–100 μM), but not by dextromethorphan (10–100 μM) or noscapine (10–100 μM), while those evoked by exogenous NKA (10–300 nM) were augmented by these drugs. The results indicate that in guinea-pig isolated bronchial muscle, dextromethorphan inhibited both neurally-mediated responses but not those to the exogenously applied agent. Tipepidine caused an inhibition similar to the non-cholinergically mediated response of dextromethorphan, it also caused a more profound inhibition of the cholinergically mediated response and selectively antagonized ACh. Noscapine had no effect.