bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-dependent decrease in rat plasma amino acids after acute administration of ethanol
Authors: Hagman Mats , Eriksson Tomas
Published: April 2011

Male rats were given three different doses of ethanol in i.p. injections (0.66, 1.33 and 200 g kg−1). A dose-dependent decrease in the concentrations of most plasma amino acids was observed. For the total amino acid concentration this decrease was 5, 16 and 22%, respectively, compared with a saline-treated control group. It has previously been suggested that the oxidation of ethanol plays an important role in the amino acid decreasing effect of ethanol. In this study the lowest dose used (0.66 g kg−1) was calculated to be high enough to keep the enzyme systems involved in ethanol oxidation saturated during the 60 min course of the experiment. The observation that the ethanol-induced decrease in plasma amino acid levels was more pronounced with higher ethanol doses indicates that not only the oxidation of ethanol but also ethanol itself is important in the effect of ethanol on plasma amino acid concentrations.
Effect of gamma-irradiation on disposition of the local anaesthetic, carbisocaine in rabbits
Authors: Kállay Z , Ďurišová M , Trnovec T , Svoboda V
Published: April 2011

14C Labelled carbisocaine, a local anaesthetic agent, has been administered intravenously in a dose of 2 mg kg−1 to rabbits 7 days after whole-body 60Co gamma-irradiation with a dose of 5 Gy (1.9 Gy min−1) and to control rabbits. The plasma carbisocaine concentration-time courses were approximated by biexponential equations. The estimated pharmacokinetic parameters obtained when the data were fitted to an open two-compartment model were significantly different for the irradiated group relative to control animals, indicating a radiation-induced slower elimination rate of carbisocaine: AUC: 0.37 vs 0.29% dose min mL−1, CLtot: 109.8 vs 155.4 mL min−1, Vdss: 27.6 vs 33.2 mL kg−1, kel: 0.0259 vs 0.0307 min−1, MRT: 251.7 vs 214.6 min. The total excreted amount of 14C radioactivity in the irradiated group was lower in comparison with controls: 6.5 vs 8.7% in bile and 18.3 vs 23.7% in urine. However, lower carbisocaine concentrations were recorded in the heart, lungs, liver, and kidneys of irradiated rabbits compared with controls.
Evaluation of contraction time and recovery period as a parameter in the calcium antagonistic action on the K+-depolarized rat duodenum
Authors: Öztürk Yusuf , Altinkurt Orhan , Yildizoǧlu-Ari Nuray , Altan V Melih
Published: April 2011

Verapamil, nifedipine, phentolamine, tolazoline, gentamicin and neomycin inhibited calcium-induced contractions of K+-depolarized duodenum of the rat by shifting the concentration-response curves to the right. Non-competitive inhibitions were observed with trifluoperazine, lidoflazine, procaine and tetracaine. Lanthanum behaved as a partial agonist in this preparation, while nitroprusside was ineffective. Contraction times in the presence of the antagonists and recovery time of the Ca2+ responses after the removal of the antagonists from the bathing medium were evaluated. From the findings, it is suggested that the contraction time and the time required for tissue recovery after removal of a Ca2+ antagonist are parameters making K+-depolarized rat duodenum a potential tool for the evaluation of the pharmacological effects of Ca2+ antagonists.
1H NMR as an analytical tool for the investigation of hydrolysis rates: a method for the rapid evaluation of the shelf-life of aqueous solutions of drugs with ester groups
Authors: Ferdous Abu J , Dickinson Noel A , Waigh Roger D
Published: April 2011

The rate of hydrolysis of esters of primary and secondary alcohols can be determined quickly and easily by 1H NMR in aqueous solution, provided that the water signal is suppressed by the WATR (Water Attenuation by T2 Relaxation) method. To evaluate this approach, Arrhenius plots have been constructed for hydrolysis of acetylcholine, carbachol and atropine, and the effect of pH on the hydrolysis of procaine has been determined over a limited range. The results agree well with literature values for rate constants.
N
G-Monomethyl-l-arginine and NG-nitro-l-arginine inhibit endothelium-dependent relaxations in human isolated omental arteries
Authors: Vila J , Esplugues J V , Martinez-Cuesta M A , Martinez-Martinez M C , Aldasoro M , Flor B , Lluch S
Published: April 2011

The L-arginine analogues NG-monomethyl-l-arginine (l-NMMA, 10−4  m) and NG-nitro-L-arginine methyl ester (l-NAME, 10−4  m), which specifically inhibit the synthesis of nitric oxide from l-arginine, significantly reduced acetylcholine-induced endothelium-dependent relaxations in rings of human omental arteries. The inhibitory potency of l-NMMA and l-NAME was similar. Addition of l-NMMA or l-NAME to the organ bath did not induce any significant changes in the resting tension of the tissues. The effects of l-NMMA were reversed by l-arginine (3 × 10−4  m). The l-NMMA enantiomer, d-NMMA (10−4  m), did not influence either the basal tone of the preparation or the relaxing effects of acetylcholine. Arterial relaxations induced by sodium nitroprusside (10−6  m) were not influenced by incubation with l-NMMA or l-NAME. These results suggest that endothelium-dependent relaxations in human omental arteries are mediated by the endogenous and substrate-specific generation of nitric oxide from l-arginine.
Theophylline reduces pulmonary eosinophilia after various types of active anaphylactic shock in guinea-pigs
Authors: Tarayre J P , Aliaga M , Barbara M , Malfetes N , Vieu S , Tisne-Versailles J
Published: April 2011

The action of theophylline was studied on the inflammatory reaction obtained in bronchoalveolar lavage fluid 24 h after an active anaphylactic shock had been induced by ovalbumin inhalation in conscious sensitized guinea-pigs. The compound was administered twice by intraperitoneal administration after the anaphylactic reaction at a dose of 50 mg kg−1. When the guinea-pigs were sensitized by intramuscular injection of 30 mg kg−1 ovalbumin or by ovalbumin aerosol, theophylline reduced the number of eosinophils and mononuclear cells in the fluid. When animals were sensitized by intramuscular injection of 30 mg kg−1 ovalbumin mixed with Freund's complete adjuvant, treatment with the xanthine derivative decreased only the number of eosinophils. In the three models theophylline did not modify significantly the number of neutrophils. Thus theophylline always reduced pulmonary eosinophilia irrespective of the mode of sensitization used to induce anaphylactic shock.
Transport characteristics of ceftibuten, cefixime and cephalexin across human jejunal brush-border membrane
Authors: Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi , Shiroto Hiroshi , Kondo Yukifumi , Uchino Jun-Ichi
Published: April 2011

The transport characteristics of orally active cephalosporins, ceftibuten, cefixime and cephalexin have been examined using brush border membrane vesicles isolated from human jejunum. In the initial uptake of ceftibuten, the stimulation and overshoot phenomena were observed in the presence of an inward H+ gradient. Effects of H+ gradient on the uptake of cefixime and cephalexin were low and no overshoot was observed. These transport characteristics, especially uphill transport phenomena, were in agreement with previous results obtained from rat intestinal brush-border membrane vesicles and suggest that these β-lactam antibiotics are absorbed by different transport systems, despite their similar molecular structures.
A novel bradykinin antagonist with improved properties
Authors: Lammek Bernard , Wang Yi-Xin , Gavras Irene , Gavras Haralambos
Published: April 2011

Acylation of the N-terminus of [d-Arg0, Hyp3, Thi5.8, d-Phe7] bradykinin with 1-adamantanecarboxylic acid results in an analogue with enhanced potency of at least 33-fold. The new antagonist has potential as a pharmacological tool in the investigation of the role of endogenous bradykinin in cardiovascular regulation.
The Site of Inversion of R(–)-Ibuprofen: Studies Using Rat In-situ Isolated Perfused Intestine/liver Preparations
Authors: Jeffrey Phillip , Tucker Geoffrey T , Bye Alan , Crewe H Kim , Wright Paul A
Published: April 2011

The site of metabolic inversion of R(–)-ibuprofen to the pharmacologically active S(+)-enantiomer has been investigated using an array of in-situ rat perfused organ preparations allowing vascular perfusion (55–60 min) of the separate or combined intestine and liver. After addition of R(–)-ibuprofen (20 mg kg−1 body weight) to the closed (static) lumen of isolated 25 cm lengths of duodenum, jejunum or ileum, and single-pass vascular perfusion, both isomers were measured in the lumen and in vascular perfusate plasma (mean plasma AUC values (±s.d., μg mL−1 min, n = 5) R(–)-ibuprofen: 1669±115 (duodenum), 1687 ± 203 (jejunum), 2061 ±188 (ileum); S(+)-ibuprofen: 23 ± 6 (duodenum), 14 ±5 (jejunum), 26±1 (ileum)). Addition of the same dose of 5(+)-ibuprofen to the jejunum (n = 5) resulted in AUC values of 1864 ± 238 for 5(+)-ibuprofen and 6±3 for R(–)-ibuprofen. After addition of R(–)-ibuprofen (30 μg mL−1) to the recirculating vascular perfusate (100 mL) of the entire small intestine (n = 6) AUC values were 1647 ± 34 for R(–)-ibuprofen and 13 ± 3 for S(+)-ibuprofen. The same dose of R(–)-ibuprofen to combined intestine/liver (n = 6) and liver only preparations (n = 6) gave AUC values of 1011 ± 25 and 1021 ± 49 for R(–)-ibuprofen and 220 ± 28 and 238 ± 22 for 5(+)-ibuprofen, respectively. In all experiments, except those involving perfusion of the combined intestine/liver and the liver, the concentrations of the isomer opposite to that administered could be accounted for solely by the level of enantiomeric impurity (1·3% for R(–)-ibuprofen and 0·6% for S(+)-ibuprofen). We conclude that inversion of R(–)-ibuprofen to the S(+) antipode occurs in the liver but does not occur on either mucosal or serosal sides of the small intestine of the rat.
Rectal Bioavailability of Water-Soluble Drugs: Sodium Valproate
Authors: Margarit María Victoria , Rodriguez Inés Carmen , Cerezo Antonio
Published: April 2011

The influence of adjuvants in suppository formulations on the release and absorption of sodium valproate, a water soluble anti-epileptic, was analysed in order to determine the optimal formula for rectal administration. Three formulations were prepared with Suppocire AS2(formula I), Aerosil R 972 (formula II) or Span 80 (formula III). In-vivo and in-vitro release-diffusion studies were performed using white laboratory rabbits as the experimental model. The adjuvants decreased the percentage release of valproic acid to 96·7% (formula I) and 84·1% (formula II), and delayed peak release-diffusion concentration (210 and 150min, respectively, with formulas II and III in comparison with 120 min with formula I). Their effect on bioavailability was observed as an increase in plasma levels of the active substance, with areas under the plasma concentration/time curve of 396·26 and 306·64 μg h mL−1 (formulas II and III, respectively) and 243·28 μg h mL−1 (formula I). The time to peak plasma concentration was also delayed with peaks at 30, 55 and 50 min with formulas I, II and III, respectively.
The influence of sampling chamber dimensions on aerosol particle size measurement by cascade impactor and twin impinger
Authors: Fults K , Cyr T D , Hickey A J
Published: April 2011

The influence of the sampling chamber dimensions upon particle size estimation by cascade impaction has been investigated and compared with measurements by the twin impinger. Aerosols of salbutamol and disodium fluorescein (DF) were generated from pressurized metered dose inhalers. The mass median aerodynamic diameter (MMAD) by the Andersen Impactor for salbutamol ranged from 2·0 to 2·8 μm with geometric standard deviations (g.s.d.) of 1·7 to 2·4. These observations were independent of the distance travelled to the first impaction surface of the impactor and volume of the sampling chamber. The DF MMAD ranged from 5·0 to 6·9 μm with g.s.d. values of 1·7 to 1·8. Changes in droplet size within the sampling chamber may cause significant differences in particle size estimates as indicated by the cascade impaction data for DF. The respirable fraction of the salbutamol samples was similar whether determined by impaction or using the impinger. The latter device has previously been indicated to give clinically relevant estimates of respirable fraction for commercial inhalation aerosol devices.
The effect of the uptake of particles on the chemotaxis of polymorphonuclear leucocytes in-vitro
Authors: Hyde R , Lewis D A , Taylor P W
Published: April 2011

The relationship between the phagocytic uptake of latex microspheres (11 μm diam.) and the mobility of rat polymorphonuclear leucocytes (PMNLs) has been investigated in-vitro. The movement of PMNLs was found to be independent of the uptake of particles but about half of the PMNLs were not receptive to the chemo-attractant N-formylmethionyleucylphenylalanine. However, the uptake of particles was greater when particle/cell ratios were high and the greatest number of particles were carried into a cellulose nitrate filter by chemotaxis at the highest particle/cell ratio of 30:1.
Studies on antiparasitic agents: effect of the lactam nucleus substitution in the 2-position on the in-vitro activity of new 5-nitroimidazoles
Authors: Vanelle P , Maldonado J , Gasquet M , Delmas F , Timon-David P , Jentzer O , Crozet M P
Published: April 2011

The in-vitro antiprotozoal activity of a series of new 5-nitroimidazoles substituted in the 2-position via a lactam nucleus was studied. All these compounds exhibited a better effect than metronidazole and structure-activity relationships are discussed.
Endothelin-induced contractions of rat pulmonary artery are not affected by drugs acting on potassium channels
Authors: Wanstall Janet C , O'Donnell Stella R
Published: April 2011

The effects of the potassium channel opening drug, pinacidil, and the potassium channel closing drug, tetraethylammonium (TEA), on concentration-response (contraction) curves to spasmogens on rat pulmonary artery were examined. Pinacidil (3 μM) decreased, and TEA (2 Mm) increased contractions to 5-hydroxytryptamine (5-HT) more than it did to noradrenaline but contractions to endothelin −1 were only minimally affected. It is concluded that the mechanism whereby endothelin-1 contracts rat pulmonary artery differs from that of noradrenaline or 5-HT in that it does not involve membrane depolarization or calcium entry through voltage operated calcium channels.
Synthesis, Biological Evaluation and Quantitative Structure Activity Relationship Analysis of Nuclear-substituted Pargylines as Competitive Inhibitors of MAO-A and MAO-B
Authors: Ali Anmar , Robinson J B
Published: April 2011

A series of nuclear substituted derivatives of pargyline has been prepared and tested (under controlled conditions designed to measure the competitive component of the inhibition) as competitive inhibitors of MAO-A and -B. Adequate correlation of the biological data with the physicochemical constants of substituent groups was obtained only when the m- and p-substituted derivatives were considered separately. Due to the narrow range of activity displayed by the p-substituted derivates when inhibiting MAO-B, meaningful correlations were not found. However, the inhibition of MAO-B by the m-substituted derivatives required the inclusion of the Verloop L parameter for adequate correlation, suggesting that the inhibitor binding site of MAO-B is present within a cavity of more limited lateral dimensions than that present on the MAO-A surface. Inhibition of both MAO-A and -B demonstrated a parabolic relationship between inhibitory activity and π. Whereas this parabolic relationship showed a maximal value for inhibition of MAO-A (mean πo = 0·86), inhibition of MAO-B demonstrated a minimal value of π (πmin= −0·5) i.e. the optimal value of π for inhibition of MAO-B has not been achieved for this series of compounds but such would be greater than that demonstrated for MAO-A. The Hammett σ function was important or significant only in the inhibition of MAO-A by the p-substituted derivatives.
An Investigation into the Haematological Toxicity of Structural Analogues of Dapsone In-vivo and In-vitro
Authors: Coleman M D , Tingle M D , Hussain F , Storr R C , Park B K
Published: April 2011

With microsomes prepared from a single human liver, 4,4′-diaminodiphenyl sulphone (DDS), 4-acetyl-4-aminodiphenyl sulphone (MADDS), 4-acetyl-4-aminodiphenyl thioether (MADDT) and 4,4′-diacetyldiphenyl thioether (DADDT) caused significantly greater methaemoglobin formation compared with control. In-vitro in the rat, the pattern of toxicity was slightly different: DADDT was not haemotoxic, whilst 3,4′-diaminodiphenyl sulphone (3,4′DDS) and 3,3′-diaminodiphenyl sulphone (3,3′DDS) as well as DDS, MADDS and MADDT were significantly greater than control. 4,4′ Acetyl diphenyl sulphone (DADDS), 4,4′ diaminodiphenyl thioether (DDT), 4,4′-diaminodiphenyl ether (DDE) and 4,4′ diamino-octofluorodiphenyl sulphone (F8DDS) did not cause significant methaemoglobinaemia in either human or rat liver microsomes. DDS, MADDS, and MADDT were not significantly different in haemotoxicity generation in-vitro in the presence of human microsomes. In the rat in-vitro, DDS, MADDS, and 3,4′DDS did not differ significantly in red cell toxicity, and were the most potent methaemoglobin formers. The 3,3′ DDS and MADDT derivatives were both significantly less toxic compared with DDS. None of the compounds tested caused haemoglobin oxidation in the absence of NADPH in-vitro. In the whole rat, DDS, MADDS and MADDT caused significantly higher levels of methaemoglobin compared with control. None of the remaining compounds caused methaemoglobin formation which was significantly greater than control. DDS and MADDS were the most potent methaemoglobin formers tested, in-vivo and in-vitro. The 3,3′ and 3,4′DDS analogues caused no detectable haemotoxicity in-vivo. However, the plasma elimination of the 3,4′ analogue was much more rapid compared with that of DDS. Overall, there was no correlation between log k0 and increasing haemotoxicity. The use of the two-compartment system together with in-vivo studies may be applied to the evaluation of the structural features required for bioactivation of candidate antiparasitic compounds to haemotoxic metabolites by cytochrome P450 enzymes.
Importance of Two Arginine Residues in Lapemis Postsynaptic Neurotoxins: Re-examination using Acetylcholine Receptor-neurotoxin Complex Instead of Free Toxin
Authors: Mori Nobuhiro , Tu Anthony T
Published: April 2011

The role of the three arginine residues in Lapemis neurotoxin has been re-examined using an acetylcholine receptor-toxin complex. The receptor-bound neurotoxin was treated with phenylglyoxal to modify available arginine residues. The positions of the modified arginine residues were then identified from the amino acid sequences of proteolytically digested fragments of the detached neurotoxin. The result was compared with the result from modification of the free Lapemis toxin (unbound). Arg-31 and Arg-34 were not modified when Lapemis toxin was bound to receptor although they were modified when the toxin was not bound to receptor. It was concluded that Arg-31 and Arg-34 residues are involved in the toxin-receptor interaction.
In-vitro interaction of mitomycin C and streptomycin A with collagen
Authors: Ramesh D Vijaya , Sehgal Praveen K
Published: April 2011

Mitomycin C and streptomycin A were studied for their interaction with soluble collagens from sepia, fish and rat skins using UV absorption spectroscopy at pH 7·4 and 3·0 and equilibrium dialysis. Both the drugs bound to collagen as shown from association constants and could be quantitatively recovered by prolonged dialysis against water showing formation of dissociable bonds between drug and collagen. At pH 7·4, mitomycin C showed greater binding affinity than streptomycin A with collagen from all three species. The reverse trend was seen at pH 3·0. Binding capacity of sepia and fish skin collagens for streptomycin A at pH 3·0 was found to be significantly greater than for mitomycin C.
Development and Testing of Bioadhesive, Fluoride-containing Slow-release Tablets for Oral Use
Authors: Bottenberg P , Cleymaet R , De Muynck C , Remon J P , Coomans D , Michotte Y , Slop D
Published: April 2011

The bioadhesive characteristics of tablets for oral use made from modified starch, polyacrylic acid (PAA), polyethylene glycol (PEG) and sodium carboxymethylcellulose (CMC) were investigated. Adhesion force and energy were determined in-vitro and maximal adhesion time was evaluated in-vivo in human subjects. In-vitro, PAA showed the best bioadhesive properties, followed by modified maize starch and PEG with a mol. wt of 300 000–400 000 daltons. The presence of 0·1 mg of fluoride as NaF did not lead to significant differences in adhesion force and energy for the same formulation. The in-vivo bioadhesion was not strongly correlated to the in-vitro data. PAA, despite its excellent adhesion, proved to be irritating to the mucosa. PEG with a mol. wt of 200000 daltons was subject to erosion. CMC showed good bioadhesive properties but the mechanical strength of the tablets was low. Modified maize starch tablets containing 5% (w/w) PAA and PEG with a mol. wt of 300 000 daltons proved to be the most suitable formulations for a fluoride-slow-release tablet with bioadhesive properties. In-vitro, the tablets released all of the fluoride within the 8 h period, with a high initial release. The release rate was related to the water absorption rate of the tablets. The PAA-containing formulations and the CMC formulations had the fastest release. In-vivo, fluoride levels with a minimum of 150 and a maximum of 1000 μg mL−1 were maintained for 8 h in the oral cavity. These fluoride levels were sustained significantly longer than those obtained with the administration of fourfold the amount of fluoride in the form of a fluoride-containing toothpaste. The release characteristics in-vivo exhibited a high variation. The use of bioadhesive polymers in oral pharmacotherapy seems promising.
5-Oxygenated N-Alkyl-and N,N-Dialkyl-2-amino-1-methyltetralins. Effects of Structure and Stereochemistry on Dopamine-D2-receptor Affinity
Authors: Grol Cor J , Nordvall Gunnar , Johansson Anette M , Hacksell Uli
Published: April 2011

The ability of a series of stereochemically well-defined 5-oxygenated 2-aminotetralins, consisting of dopamine-receptor agonists and antagonists, to displace [3H]spiperone and [3H]N-propylnorapomor-phine (NPA) from calf-caudate dopamine receptor sites has been evaluated in-vitro. In addition, the partition coefficients of the compounds were determined to measure their lipophilicity. The data were compared with previously obtained in-vivo biochemical data (dopa accumulation in reserpine pretreated or non-pretreated rats). Compounds with 2S-configuration and a C5-hydroxy substituent have the highest affinity for NPA-binding sites and such derivatives also have the highest potency in-vivo. The 2R-derivatives are less efficacious and their affinity for NPA- and spiperone binding sites is influenced by their lipophilicity. On the basis of these results, a model is proposed in which the antagonists form two, and the agonists form three, strong intermolecular bonds with the D2-receptor. According to this model, the agonists, but not the antagonists, are able to donate a hydrogen bond from the phenolic hydroxyl to the receptor.
The Fluoroquinolones Exert a Reduced Rate of Kill Against Enterococcus faecalis
Authors: Lewin C S , Morrissey I , Smith J T
Published: April 2011

The bactericidal activities of ciprofloxacin, ofloxacin and DR-3355 have been investigated against Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis over 24 h. The three fluoroquinolones were found to be rapidly bactericidal against the staphylococci, killing over 99% of the bacteria during the first 3 h of exposure with a further reduction in viability of approximately one logarithm occurring over the next 21 h. In contrast, the fluoroquinolones displayed a much slower rate of kill against E. faecalis, as little or no bactericidal activity was detected over the first 3 h for both E. faecalis ATCC 19433 and a clinical isolate. At 6 h all three of the drugs were bactericidal against the enterococci although the amount of kill was not as great as against the staphylococci. However, at 24 h the amount of kill obtained with all three drugs was similar to that obtained for staphylococci exposed to these drugs. Ciprofloxacin, ofloxacin and DR-3355 were not active against E. faecalis ATCC 19433 in phosphate buffered saline and therefore require cell division for their bactericidal activity against this species.
Cardiovascular Effects of Intracerebroventricular Injections of (±)-Nebivolol and its Enantiomers—a Comparison with those of Metoprolol in the Rat
Authors: Midol-Monnet M , Davy M , Heimburger M , Beslot F , Cohen Y
Published: April 2011

The cardiovascular effects of (±)-nebivolol, a potent β1-adrenoceptor antagonist, and its enantiomers, (+)-nebivolol (SRRR) and (–)-nebivolol (RSSS) in normotensive anaesthetized rats, have been investigated using metoprolol as a reference substance. The drugs decreased blood pressure and heart rate immediately after i.c.v. injection. These effects paralleled the β-blocking potencies ((+)- > (±)- > (–)-nebivolol). Metoprolol induced a weaker hypotension than (±)-nebivolol, and a long-lasting reduction in stroke volume. As reported after i.v. administration, (±)-nebivolol and isomers by the i.c.v. route decreased peripheral vascular resistance following i.c.v. administration while metoprolol increased it. These effects are centrally mediated since cardiovascular responses to isoprenaline i.v. remained unchanged.
The use of electron spin resonance to measure micro viscosity
Authors: Gebre-Mariam Tsige , Armstrong N Anthony , James Kenneth C , Evans Jeffrey C , Rowlands Christopher C
Published: April 2011

The viscosities of a series of mixtures of glycerol and water were measured by electron spin resonance (ESR), photon correlation spectroscopy and Ostwald viscometry. Close agreement was obtained between the last two methods but viscosity as measured by ESR was always significantly lower. The difference, the magnitude of which depended on the spin probe used, was attributed to interaction between water and glycerol. Similar results were obtained using water-sorbitol and water-sucrose mixtures.
Salivary excretion of mexiletine in normal healthy volunteers
Authors: Katagiri Yoshihiro , Nagasako Sadao , Hayashibara Masakazu , Iwamoto Kikuo
Published: April 2011

To investigate the kinetics and correlation between serum and saliva levels of mexiletine, serum (total and unbound) and saliva drug concentration-time courses have been analysed in five normal healthy volunteers after administration of a single oral dose (200 mg) of the drug. Mexiletine levels in saliva were always higher than those in serum. The drug concentration-time curve in each sample was analysed according to the non-linear least squares regression program MULTI, for a two-compartment model with first-order absorption. The saliva drug concentration in the post-absorption phase was found to be well correlated with either corresponding serum total or serum unbound drug level in four of the subjects. Although there was a large inter-individual variation in the ratio of saliva to serum drug concentrations as well as in the pharmacokinetic parameters, an almost consistent ratio was obtained in each individual.
The effect of a 5-HT3-antagonist on the ileal brake mechanism in the rat
Authors: Brown Nicola J , French S J , Rumsey R D E , Read N W
Published: April 2011

Studies have been carried out on 7 male adult rats to investigate how the action of the selective 5-HT3 receptor antagonist, granisetron, influences gastrointestinal transit under control conditions and when it is delayed by ileal infusion of lipid. Stomach to caecum transit time (SCTT) was measured using environmental hydrogen analysis. Subcutaneous administration of granisetron (BRL 43694, 40 μg kg−1) significantly delayed the passage of the head of the baked bean meal through the stomach and the small intestine under control conditions (P < 0·05). The same compound, however, significantly reversed the delay in SCTT induced by ileal infusion of lipid (P < 0·001). These apparently paradoxical results may be rationalized by postulating inhibition of receptors on afferent nerves initiating reflexes that both accelerate and delay transit.
The effect of 8-cyclopentyl-1,3-dipropylxanthine on the development of cyclosporin-induced acute renal failure
Authors: Panjehshahin M R , Chahil R S , Collis M G , Bowmer C J , Yates M S
Published: April 2011

The effect of the selective A1-adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 0·1 mg kg−1 i.v.) administered twice daily to rats has been assessed on the development of renal dysfunction induced by four daily injections of cyclosporin (60 mg kg−1 i.p.). The series of cyclosporin injections resulted in a polyuria accompanied by a 64–70% increase in plasma urea and creatinine concentrations and a 50% reduction in inulin clearance. However, cyclosporin administration resulted in no change in p-aminohippurate clearance nor was there any evidence of tubular necrosis or vascular damage. CPX treatment did not improve any index of renal function perturbed by cyclosporin. The findings provide evidence that adenosine does not play a role in the pathophysiology of cyclosporin nephrotoxicity.
Calcium Antagonism by KB-2796, a New Diphenylpiperazine Analogue, in Dog Vascular Smooth Muscle
Authors: Iwamoto T , Morita T , Sukamoto T
Published: April 2011

The effects of KB-2796, a new diphenylpiperazine analogue, on [3H]nitrendipine ([3H]NTD) binding, KCl-induced contraction and 45Ca influx has been examined in dog vascular smooth muscle, and compared with those of other diphenylpiperazines. In the binding study, [3H]NTD was found to bind with a high affinity to a single class of sites on aortic membranes (Kd = 0·41 Nm and Bmax = 31 fmol(mg protein)−1). KB-2796 inhibited specific [3H]NTD binding in a concentration-dependent manner, with a Ki value of 0·34 μm. The other diphenylpiperazine derivatives such as flunarizine and cinnarizine also inhibited binding in the same manner. Also, in the contraction study, all the diphenylpiperazines antagonized the 50 Mm KCl-induced contraction of isolated mesenteric arteries concentration-dependently. The IC50 values of the compounds for KCl-induced contraction correlated strongly with the respective Ki values obtained in the [3H]NTD binding study. In the 45Ca influx study, KB-2796 also effectively inhibited KCl-induced 45Ca influx in mesenteric arteries, with an IC50 value of 0·14 μm. This was close to the IC50 value found in the KCl-induced contraction study. These findings suggest that calcium antagonism by KB-2796 is responsible for its vasorelaxing action in vascular smooth muscle.
The Effect of α1-Acid Glycoprotein on the Pharmacological Activity of α1-Adrenergic Antagonists in Rabbit Aortic Strips
Authors: Chiang Janie , Hermodsson Görel , Øie Svein
Published: April 2011

The pharmacological activity of three α1-adrenergic antagonists, prazosin, tiodazosin and WB4101 has been studied in the presence and absence of 20 μ m α1-acid glycoprotein (AAG) in rabbit aortic strips, and measured as the ability to increase the EC50 value of the α1-adrenergic agonist phenylephrine. For all three drugs, the presence of AAG diminished the pharmacological activity when compared with equivalent unbound concentrations in the absence of AAG. In the presence of AAG the EC50 value of phenylephrine at 5·69 Nm unbound prazosin was on average 47% lower than in the absence of AAG (P < 0·002), at 122 Nm unbound tiodazosin, 39% lower (P < 0·01), and at 25·6 Nm unbound WB4101, 68% lower (P < 0·002). Albumin showed no ability to modify the α1-adrenergic blocking activity of prazosin (P > 0·1). The EC50 value for phenylephrine in the absence of antagonists was not affected by AAG. The effect of AAG on the antagonistic activity of prazosin was concentration-dependent with a maximum suppression of prazosin activity of 79% and with a half-maximum concentration of 1·1 μm AAG. AAG significantly decreased prazosin's ability to reduce α1adrenergic stimulation of calcium influx (P < 0·05), while it had no effect on prazosin's ability to decrease α1-adrenergic-stimulated formation of inositol phosphate. These results suggest that the effect of AAG on adrenoceptors appears to act selectively via α1a-receptors. Consistent with these observations was the observation that WB4101, a selective α1a-antagonist was more affected by AAG than was prazosin or tiodazosin.
The Design of Analytical Methods for Use in Topical Epidermal Growth Factor Product Development
Authors: DiBiase M D , Rhodes C T
Published: April 2011

Data from a reverse phase gradient elution HPLC assay for human epidermal growth factor (EGF) was compared and correlated with data obtained from a competitive heterogeneous radioimmunoassay (RIA). The RIA was established to measure very low concentrations of EGF in formulation drug release and compatibility studies. The HPLC assay, capable of resolving parent and possible modified or fragmented forms of EGF isolated from human urine, was studied as a potential development tool for stability and final product evaluation. As independent analytical methods, the HPLC and the RIA procedures produced correlated results when quantifying freshly prepared and certain degraded samples of EGF. The capacity of the HPLC method to serve as a stability indicating assay was examined. Degradation of EGF was induced by storage in 0·05 m phosphate buffer pH 7·4 at 25, 37 or 50°C. The same three degradation products were detected at each temperature by the HPLC method, one of which was identified as l-isoaspartyl EGF.
Effect of Imipramine on the Membrane Anisotropy and on the Phospholipid Methylation in the Central Nervous System of the Rat
Authors: Melzacka Miroslawa , Nocon Halina
Published: April 2011

An ex-vivo and in-vitro study of the effects of imipramine on the membrane anisotropy and phospholipid methylation in the rat cortical membranes was carried out. A comparative study of the membrane fluidity in various brain regions indicated different basal anisotropy of the areas and different reaction of these membranes to imipramine. It was found that imipramine when given to rats chronically (14 × 10 mg kg−1, i.p.) or added externally to the cortical membranes of naive rats or rats treated with a single dose of imipramine (10 mg kg−1, i.p.) decreased the anisotropy of cortical membranes. Chronic imipramine produced some changes of the membrane architecture in the cortex, whereas imipramine in different concentrations did not fluidize these membranes in-vitro. Imipramine in concentrations corresponding to its mean concentration in the rat brain after administration at a dose of 10 mg kg−1 i.p., potentiated phospholipid methylation in the cortical membranes of naive rats and rats receiving imipramine in a single dose of 10 mg kg−1 i.p. in an in-vitro study, whereas the prolonged administration of imipramine decreased the sensitivity of phospholipid methyltransferases to the stimulating effect of the drug in-vitro.
Impaired Prednisolone Sensitivities of the Endocrine System and Peripheral-blood Lymphocytes are Closely Related to Clinical Incidence in Renal Transplantation
Authors: Hirano Toshihiko , Oka Kitaro , Sakurai Etsuo , Tamaki Tohru , Kozaki Masami
Published: April 2011

Endocrine- and immune-responses to prednisolone and their relation to clinical incidence were assessed in 19 renal transplant recipients. All of the patients were treated with prednisolone and cyclosporin. Response of the hypothalamic-pituitary-adrenal (HPA) system to prednisolone was evaluated by measuring serum Cortisol concentration. Cortisol concentration before transplantation was 126·7 ± 38·6 ng mL−1, while it decreased to 4·1 ±2·5 ng mL−1 within the period characterized by a cumulative dose of prednisolone from 300 to 700 mg. A statistically significant high incidence (P < 0·01) of acute rejections was observed in low HPA responders; (mean Cortisol concentration during prednisolone treatment exceeded 3·0 ng mL−1), 6 of 12 with a low HPA response to prednisolone showed signs of rejection, while none of the 7 with a high HPA response showed signs of rejection. The concentrations of prednisolone suppressing the in-vitro response of pretransplant lymphocytes to concanavalin A by 50% (ID50) were determined. Lymphocytes from 8 patients were extremely insensitive (ID50 > 500 ng mL−1), and 5 of the 8 showed signs of rejection. Lymphocytes from the other 11 patients showed high sensitivity (ID50 < 500 ng mL−1), and only one of those showed signs of rejection. Thus, a significantly high incidence of rejection was observed in low lymphocyte-responders to prednisolone (P < 0·05). The results suggest that an insensitive endocrine response to prednisolone correlates with an impaired lymphocyte response to the steroid, and that both of the indices are related to occurrence of rejection. Evaluation of these pharmacodynamic parameters in combination may serve as a guideline for successful immunosuppressive therapy in renal transplantation.
In-vitro Interaction of a Novel Immunosuppressant, FK 506, and Antacids
Authors: Steeves M , Abdallah H Y , Venkataramanan R , Burckart G J , Ptachcinski R J , Abu-Elmagd K , Jain A K , Fung F , Todo S , Starzl T E
Published: April 2011

The effect of selected antacids on the amount of FK 506 in solution in simulated gastric juice has been studied. FK 506 (2–5 mg) was incubated in 100 mL simulated gastric fluid (SGF) with the equivalent of 500 mg of various antacids. The addition of Mylanta and Turns resulted in 14 and 30% loss of FK 506, respectively, in 24 h; 98% loss was observed in 12 h in the presence of Mag-Ox; 100% loss was observed in the presence of magnesium oxide powder in 2 h. The loss of FK 506 from these solutions appears to be due to a pH mediated degradation of FK 506. The addition of aluminium hydroxide gel USP (Roxane) to the FK 506 solution resulted in a 35% loss within 2 min but no further loss was noted for 24 h, indicative of adsorption of FK 506. These results suggest that until additional in-vivo studies are carried out, it is prudent not to dose FK 506 and antacids at the same time to avoid potential interactions.
The Effect of Pimobendan on Myocardial Mechanical Function and Metabolism in Dogs: Comparison with Dobutamine
Authors: Ichihara Kazuo , Abiko Yasushi
Published: April 2011

The effect of pimobendan, a newly developed cardiotonic agent, on myocardial mechanical function and energy metabolism has been examined in the dog heart, and compared with that of dobutamine. Either saline, vehicle for pimobendan, dobutamine (0·3 and 1 μg kg−1), or pimobendan (0·3 and 1 mg kg−1) was injected intravenously. Dobutamine and pimobendan both increased the first derivative of left ventricular pressure and percent segment shortening, indicating their positive inotropic action. After 2 min of dobutamine injection, or after 20 min of pimobendan injection, the myocardium was removed, and used for determination of the tissue levels of metabolites of energy and carbohydrate metabolism. In genera), all metabolic parameters measured were not changed by either dobutamine or pimobendan injection. In animals with aortic constriction for 10 months, dobutamine and pimobendan injections did not alter the myocardial energy and carbohydrate metabolism. Although dobutamine and pimobendan increased the cardiac mechanical function, they did not disturb the myocardial energy and carbohydrate metabolism.
Influence of Intravenous Administration Set Composition on the Sorption of Isosorbide Dinitrate
Authors: De Muynck C , Colardyn F , Remon J P
Published: April 2011

The influence of the composition of administration sets on the sorption of isosorbide dinitrate was investigated in-vitro. Isosorbide dinitrate solutions (250 μg mL−1) in 0·9% NaCl or 10% glucose were stored in glass containers and administered at a flow rate of 20 mL h−1. The influence of the concentration of different plasticizers (di-ethylhexylphthalate, tri-ethylhexyltrimelitate) in polyvinylchloride tubings was determined. Polybutadiene tubings of different mol. wt coextruded laminates of these polybutadienes with PVC of different composition and a polyethylene tubing were evaluated. The higher the Shore hardness of the PVC tubing, the lower the sorption. The infusion fluid played an additional role only for the tubings with high Shore hardness (> 70). The sorption of isosorbide dinitrate to polybutadiene tubings of different mol. wt was less than 2·5% after 5 h and was comparable with the sorption to the polyethylene tubing. When polybutadiene/PVC laminates were used, the sorption increased significantly and was in most cases dependent on the Shore hardness of the PVC (higher Shore hardness gave lower sorptions) and on the mol. wt of the polybutadiene (lower mol. wt resulted in higher sorption). Sorption was not dependent on the type of PVC plasticizer.
Development and Evaluation of an Intracutaneous Depot Formulation of Corticosteroids Using Transcutol as a Cosolvent: In-vitro, Ex-vivo and In-vivo rat Studies
Authors: Panchagnula R , Ritschel W A
Published: April 2011

A topical delivery system has been developed using 50% Transcutol (diethylene glycol monoethyl ether) to decrease the body burden of topically administered dexamethasone and hydrocortisone. The delivery system was evaluated in-vitro using a dissolution apparatus to measure the release of steroid from the gel. In 10 h, 29·6±0–39% dexamethasone and 45·5 ±0·84% hydrocortisone was released from the formulation compared with 23·0 ±0·48 and 39·9 ±0·77%, respectively, from control formulations without Transcutol. Ex-vivo evaluation was made using rat whole skin in a diffusion cell; the amount of steroid reaching the acceptor cell was significantly less from the formulation containing Transcutol compared with controls. There was also a 2-fold increase in the retention of dexamethasone and a 3-fold increase in the retention of hydrocortisone in the skin at the end of the permeation experiments compared with control experiments. In-vivo studies were made using a formulation containing [3H]hydrocortisone applied to rat skin, followed by measurement of total radioactivity in the blood. For the Transcutol formulation the area under the blood concentration-time curve (0–96 h) was 6·06± 1·27 compared with 2·52 ± 0·43 × 106 d min−1 mL−1 h for the control formulation, indicating a 58% reduction in body burden.
Resolution and Electrophysiological Effects of Mexiletine Enantiomers
Authors: Turgeon Jacques , Uprichard Andrew C G , Bélanger Pierre M , Harron Dean W G , Grech-Bélanger Odette
Published: April 2011

Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(–)- and S-(+)-mexiletine were resolved with an optical purity > 98 % (yield ∼ 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7–30 days after coronary ligation. R-(–)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0·5 mg kg−1, 1 after 8 mg kg−1); two animals died after 1 and 8 mg kg−1, respectively; one remained unchanged even at the highest dosage (16 mg kg−1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg−1); two died after 4 and 8 mg kg−1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg−1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0·5–16·0 mg kg−1). These results suggest that R-(–)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.
Investigation of the Different Types of Opioid Receptor Involved in Electroconvulsive Shock-induced Antinociception and Catalepsy in the Rat
Authors: Jackson Helen C , Nutt D J
Published: April 2011

The effects of novel opioid antagonists on the behavioural syndrome induced by electroconvulsive shock (ECS) in rats have been examined and compared with those of the established agent naloxone. A single ECS produced catalepsy and significantly increased tail immersion response times during the 15 min following the seizure. These responses were inhibited by a low dose of naloxone (1 mg kg−1, i.p.) and also by RX8008M (16-methylcyprenorphine; 1 mg kg−1, i.p.) which blocks μ- and δ- but not κ-opioid receptor function. In comparison, the antinociception and catalepsy induced by ECS was not attenuated by the selective δ-receptor antagonist naltrindole (1 mg kg−1, i.p.). These results suggest that ECS-induced antinociception and catalepsy may be mediated by endogenous opioids acting at μ-opioid receptors and are consistent with biochemical studies showing the release of β-endorphin in both animals and man following this procedure.
Changes in K+-induced contractions in ileal longitudinal smooth muscle of guinea-pig, induced by monoiodoacetic acid
Authors: Nasu T , Narimatsu H , Shibata H
Published: April 2011

The ileal responses to 40 min [K+]o were changed in the period after administration of monoiodoacetic acid (IAA). The phasic contraction to K+ appeared in the period before the development of a rigor, after the administration of 1 mM IAA. However, the response to K+ was absent during the development of a rigor to IAA during decreasing tissue ATP concentrations.
Lung Uptake of Liposome-entrapped Glutathione After Intratracheal Administration
Authors: Jurima-Romet M , Shek P N
Published: April 2011

The intratracheal delivery of glutathione (GSH), in liposome-encapsulated form, prolongs retention of the drug in the rat lung. This study has been designed to determine the extent and zime-course of pulmonary tissue uptake of administered 14C-labelled liposomes containing [3H]GSH. Liposomes, composed of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine each with or without 30 mol% cholesterol showed a clearance >80% from the bronchoalveolar lavage, 24 h after intratracheal instillation. Lung tissue content of 14C-lipid increased with time: by 72 h, 42–56% of the administered dose was recovered from the tissue. [3H]GSH was present in pulmonary tissue in relatively constant amounts throughout the 72 h, ranging from 14–35% of the administered dose. Vesicles composed of DMPC had a low entrapment for GSH. There were only minor differences in GSH entrapment efficiency and lung tissue uptake between vesicles of the other lipid compositions.
Synthesis of Some Phenothiazine Derivatives as Potential Affinity Ligands for the Central Dopamine Receptors
Authors: Šoškić V , Maelicke A , Petrovic Gorica , Ristic Biljana , Petrović Jelena
Published: April 2011

Syntheses of several phenothiazine ligands as potential affinity probes for the D1- and D2-dopamine receptors derived from 4-(3-(10-(2-trifluorornethyl) phenothiazinyl) propyl)-1-(2-aminoethyl)-piperazine hydrochloride are described and their interactions with D1 and D2-dopamine receptors of the bovine caudate nucleus have been characterized. The bromoacetylamido-, maleinimido-, and isothiocyanato-derivatives expressed low selectivity and moderate affinity for both categories of dopamine receptors. 4-(3-(10-(2-Trifluoromethyl) phenothiazinyl)propyl)-1-(2-(isothiocyanatobenzoyl)ethyl)-piperazine hydrochloride did not discriminate among the two subclasses of the dopamine receptors, but showed an extremely strong irreversible binding to the D1-receptors and thus is promising as a highly specific affinity ligand for biochemical and pharmacological studies of the D1-dopamine receptors.