bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of the In-vitro Human Skin Permeability of Nicorandil from Animal Data
Authors: Sato Kiyoshi , Sugibayashi Kenji , Morimoto Yasunori , Omiya Harumi , Enomoto Naoyoshi
Published: April 2011

A method for estimating the in-vitro permeability of human skin to drugs, based on in-vitro permeation studies using animal skins, has been developed. The skins from hairless rats, guinea-pigs, dogs and pigs were used, with nicorandil and deionized water as model drug and solvent in a drug-donor compartment. Diffusion coefficients through the skin barrier, D, and partition coefficients from the drug-donor compartment to skin, K, of the drug, in each species, were calculated by curve-fitting the in-vitro permeation data to a diffusion equation describing the drug permeation through a homogeneous membrane, using a non-linear least squares method. Each barrier thickness, L, was measured microscopically from microtomed skin sections. A positive relationship was found between the skin permeability, Kp, and K value among the four species, but species differences in the D and L values were small in spite of the Kp values being different among the four species. A positive correlation was also observed between the calculated and experimental K values among the four species, and hence it was suggested that the main factor for the species difference in the skin permeability of nicorandil would be the difference in partitioning of the drug from vehicle to stratum corneum. As a result, it has become feasible to predict and estimate skin permeability of nicorandil in humans by substituting each parameter, extrapolated from the animal skin permeation data and partition experiments, in the diffusion equation.
Pharmacokinetic Profile of Idazoxan in the Beagle Dog
Authors: Vallès J , Pruñonosa J , Menargues A , Nomen M , Obach R
Published: April 2011

The α2-antagonist idazoxan (2- (2- (l,4-benzodioxanyl))-2-imidazoline) has been given intravenously and orally to five beagle dogs at 1, 3 and 10 mg kg−1 doses. Idazoxan plasma levels were determined by a HPLC method. After intravenous administration, a linear kinetic behaviour was obtained. Half-life and mean residence time values ranged 105·2–117·1 and 138·1–154·0 min, respectively. Total plasma clearance values and volume of distribution at steady state values ranged from 25·6–32·1 (mL kg−1) min−1 and 3·60-4·36 L kg−1, respectively. After oral administration, time to peak values averaged around 1 h. Dose normalized peak concentration values ranged 161–182 ng mL−1. Bioavailability values ranged 60–88%. Low idazoxan bioavailability has been described in other animal species and attributed to a first-pass effect.
Disposition of the Hypolipidaemic Agent, 2,3-Dihydrophthalazine-1,4-dione, in Sprague Dawley Rats
Authors: Hall Iris H , Oswald C Brent , Wyrick Steven D , Maguire James H , Shrewsbury Robert P
Published: April 2011

The disposition of [14C]2,3-dihydrophthalazine-1,4-dione, a potent hypolipidaemic agent, has been determined after both intravenous and oral administration. Both the routes of administration afforded multi-exponential disposition with an estimated t 1/2 of approximately 75 h. After oral administration, the drug was observed to be absorbed rapidly from the intestine and distributed quickly to all tissues of the body. A large quantity of the 14C-radioactivity was found in the skin and carcass. Approximately 35% of the administered radioactivity was excreted in urine after oral administration and 11% in the faeces. Approximately 66% of the radioactivity excreted in urine was the parent drug. There was evidence of an additional metabolite which accounted for 28% of the urinary radioactive excretion. The parent drug has little serum protein binding, is highly water soluble, and is probably taken up by cells by passive diffusion.
Bioavailability of intramuscular vitamin E acetate in rabbits
Authors: Pedraz J L , Calvo B , Bortolotti A , Celardo A , Bonati M
Published: April 2011

The bioavailability of α-tocopherol acetate and α-tocopherol (vitamin E) was assessed in male rabbits given 50 mg kg−1 doses according to a randomized design. After intramuscular injection of α-tocopherol acetate in colloidal aqueous solution, a mean absolute bioavailability of 65% was calculated for the acetate and 35% for the physiologically active compound, α-tocopherol. Comparison of the kinetic profiles after intravenous and intramuscular administration of the acetate and intravenous injection of α-tocopherol, revealed absorption of α-tocopherol acetate from the site of injection and hydrolysis of the acetate to be potential limiting steps in the bioavailability of α-tocopherol. Intramuscularly injected α-tocopherol acetate in olive oil (the only formulation available in a few European countries) proved completely bio-unavailable. It thus appears necessary to re-assess the utility of current vitamin E supplementation, since the only formulations available offer poor bioavailability.
Hydroxylamine dilates resistance blood vessels of the perfused rat kidney and mesentery
Authors: Moore P K , Burrows L , Bhardwaj R
Published: April 2011

Hydroxylamine (ED50 values, 47 ± 8·9 nmol and 320 ± 39 nmol) dilates resistance arterioles of the perfused noradrenaline-preconstricted rat kidney and mesentery. In this respect hydroxylamine was approximately 63 × and 320 × less potent than acetylcholine (ACh) and 15 × and 128 × less potent than nitroprusside in the two perfused organs studied. The vasodilator effect of hydroxylamine (unlike that of ACh) was unaffected by CHAPS de-endothelialization suggesting that its effect is independent of endothelium-derived relaxing factor (EDRF).
Iontophoretic transport of weak electrolytes through the excised human stratum corneum
Authors: Siddiqui Ovais , Roberts Michael S , Polack Alan E
Published: April 2011

The effect of iontophoresis on the rate of permeation of a number of therapeutically active weak acids and bases through excised human stratum corneum has been examined, over a range of pH values. It has been shown that the amount of ionized drug species present in the drug solution is an important factor in the delivery of acids and bases by this route and that the molecular weight of the drug does not influence the rate of delivery by iontophoresis.
Effect of Particle Shape on the Mixing of Powders
Authors: Wong L W , Pilpel N
Published: April 2011

Mixtures were prepared containing 200 g of 600 μm lactose and 0.5 g of 3 μm calcium carbonate of different particle shapes using a Y cone mixer. Measurements were made of the time required to achieve the acceptable standard deviation of mixing σA and of the segregation that occurred on subsequently vibrating the mixtures. The time taken to achieve σA increased with the irregularity of the particles of both components and the mixtures containing irregular particles segregated less on vibration.
Macrophage Activation for Antitumour Function by Muramyl Dipeptide-protein Conjugates
Authors: Tabata Yasuhiko , Ikada Yoshito
Published: April 2011

A muramyl dipeptide (MDP) has been conjugated directly with various proteins by means of a water-soluble carbodiimide. The enhancement of the antitumour activity of mouse peritoneal macrophages by the MDP-protein conjugates has been investigated to assess the ability of the proteins for targeting MDP to the macrophages. These were activated to inhibit the in-vitro growth of tumour cells much more effectively, when immunoglobulin (IgG), fibronectin (FN), and gelatin conjugates were used than when MDP was used alone. The minimum amount of MDP in both the MDP-gelatin and the MDP-IgG conjugates necessary for macrophage activation was approximately 2000 times lower than the amount of free MDP needed. The macrophages activated by the conjugates exhibited growth inhibitory activity against phenotypically diverse tumour cells. The activity induced by the MDP-gelatin conjugate was higher than that of the MDP-IgG conjugate over the range of MDP concentrations, regardless of the isoelectric point of the gelatin used. When MDP was conjugated with bovine serum albumin (BSA), the antitumour activity of macrophages was reduced as the amount of BSA conjugated increased. With both free MDP and MDP-protein conjugates, the macrophages were more strongly activated, the longer they were pretreated. However, less pretreatment time was needed to potentiate macrophage activation by the MDP-gelatin conjugate than by free MDP. Also, the macrophages pretreated with the MDP-gelatin conjugate could maintain their activated state for longer than those pretreated with free MDP. It is concluded that gelatin is an effective carrier protein for the targeting MDP to macrophages, resulting in their activation.
Influence of Lignocaine on Plasma Protein Binding and Pharmacokinetics of Verapamil in Dogs
Authors: Belpaire Frans M , de Rick Andre , Bourda Alain , de Smet Frits , Rosseel Marie-Therese , Bogaert Marc G
Published: April 2011

The effect of lignocaine (lidocaine) on the plasma protein binding of verapamil has been studied in-vitro and in-vivo in dogs. The binding of verapamil was ca 85%. In-vitro addition of lignocaine at therapeutic concentrations displaced verapamil from its plasma binding sites. Lignocaine in this regard was equipotent with tris(2-butoxyethyl)phosphate, suggesting an interaction at the level of α1-acid glycoprotein binding sites. On in-vivo administration of 4 mg kg−1 in a bolus to dogs in which steady state concentrations of verapamil were present, the free fraction of verapamil increased transiently. During the lignocaine maintenance infusion, it then decreased to a level higher than that before administration of the local anaesthetic. The free verapamil concentrations increased suddenly upon the administration of the lignocaine loading dose, and then returned to values slightly higher than those before lignocaine. After a bolus injection of verapamil during a lignocaine infusion, the verapamil total plasma concentrations were lower than during a saline infusion, but the free concentrations were not different. The volume of distribution of verapamil was increased, whereas the blood clearance had not changed; the lignocaine infusion did not change the hepatic blood flow, as measured by indocyanine green clearance. These results show that lignocaine displaces verapamil in-vitro and in-vivo from its plasma protein binding sites, but the ensuing pharmacokinetic changes do not lead to significant changes in free verapamil concentrations.
Effect of time of dosing relative to a meal on the raft formation of an anti-reflux agent
Authors: Washington Neena , Greaves Jane L , Wilson Clive G
Published: April 2011

Gamma scintigraphy was used in twelve healthy volunteers to establish whether the time of dosing of Liquid Gaviscon relative to a meal influenced its therapeutic action. Indium-113m labelled Liquid Gaviscon was administered to fasted subjects, 30 min after a technetium-99m labelled meal or immediately before ingestion of the meal. The time for 50% of the Gaviscon to empty from the stomach was 0.36 ± 0.13 h, 3.10 ± 0.31 h and 0.68 ± 0.04 h (s.e.m.), respectively. The preparation was found to empty rapidly from the fasted stomach and could not be floated on a meal consumed subsequently. For raft formation to occur, Liquid Gaviscon should be taken 30 min after a meal.
Gastric mucosal cytoprotection in the rat by naftidrofuryl oxalate
Authors: Salim Aws S
Published: April 2011

Ischaemic gastric mucosal injury was assessed in the rat by measurement of the area of the injury produced after 6 h by reserpine (5 mg kg−1 i.p.) or 5-hydroxytryptamine (5-HT) (50 mg kg−1 i.p.). Pretreatment with naftidrofuryl 1 mL, 1% by gavage significantly (P < 0001) protected the rat stomach against the reserpine (24 ± 2.7 mm2 vs 40 ± 4.7 mm2, mean ± s.e.m., n = 10) and 5-HT injury (11.4 ± 1.7 mm2 vs 27 ± 4.1 mm2, mean ± s.e.m., n = 10). Naftidrofuryl 1 mL 2% by gavage was more effective (P < 0.001) in this respect and mucosal injury only developed in 50% of rats injected with reserpine (9.4 ± 1.1 mm5) and 30% of those injected with 5-HT (3.2 ± 0.4 mm2). Administration of naftidrofuryl 1 mL 5% by gavage completely protected the rat against both the reserpine- and 5-HT-induced acute gastric mucosal injury. This protection was not associated with any significant influence on the H+ output.
α2-Adrenoceptor-mediated Inhibitory and Excitatory Effects of Detomidine on Rat Gastric Acid Secretion
Authors: Blandizzi C , Bernardini M C , Natale G , Del Tacca M
Published: April 2011

The effects of the selective α2-adrenoceptor agonist detomidine on gastric acid secretion from pylorus-ligated and stomach-perfused rats have been investigated. In pylorus-ligated rats i.p. injection of detomidine markedly inhibited acid secretion, this effect being prevented by yohimbine or idazoxan. Under the same conditions, idazoxan significantly increased secretion in a dose-independent fashion. In non-vagotomized and vagotomized stomach-perfused rats i.p. detomidine stimulated acid secretion: this excitatory effect was antagonized by idazoxan. The present results suggest that both inhibitory and excitatory gastric secretory effects of detomidine are mediated by α2-adrenoceptors on cholinergic and adrenergic nerves, respectively. The stimulant activity of idazoxan on gastric secretion from pylorus-ligated rats may be interpreted in terms of increased excitatory vagal tone following the blockade of inhibitory α2-adrenoceptors.
Inhibition of gastric H+, K+-ATPase by chalcone derivatives, xanthoangelol and 4-hydroxyderricin, from Angelica keiskei Koidzumi
Authors: Murakami S , Kijima H , Isobe Y , Muramatsu M , Aihara H , Otomo S , Baba K , Kozawa M
Published: April 2011

Two chalcone derivatives, xanthoangelol (I) and 4-hydroxyderricin (II) isolated from Angelica keiskei Koidzumi, inhibited pig gastric H+, K+ -ATPase with IC50 values of 1.8 and 3.3 μM, respectively. The inhibition by I or II was competitive with respect to ATP and was non-competitive with respect to K+. I and II also inhibited K+, stimulated p-nitrophenyl phosphatase, with IC50 values of 1.3 and 3.5 μM, respectively. Proton transport in-vitro was inhibited by I or II, in a dose-dependent manner. I at 100 mg kg−1, i.p. significantly inhibited acid secretion and the formation of stress-induced gastric lesions. These results suggest that the antisecretory effect of I is due to the inhibition of gastric H+, K+-ATPase.
The Effect of Some Anti-inflammatory Agents on Elastase Release From Neutrophils In-vitro
Authors: Adeyemi E O , Chadwick V S , Hodgson H J F
Published: April 2011

In view of the potential role of released polymorphonuclear leucocyte elastase in causing tissue damage, the effect of commonly used anti-inflammatory drugs on elastase release from neutrophils has been studied in-vitro. Elastase release from neutrophils exposed to the synthetic bacterial cell wall peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (10−6 M) was quantitated using a radiometric immunoassay and a functional assay of elastase. Prednisolone and non-steroidal anti-inflammatory drugs inhibited elastase release at concentrations from 0.1 mM-0.1 nM. No inhibition by sulphosalicylic acid, D-penicillamine or chloroquine sulphate was observed. The clinical relevance of these findings is discussed.
The effect of chronic captopril administration on hepatic blood flow of the rat
Authors: Bar-Meir Simon , Prigojin Haia , Bruck Rafael , Krepel Zipora , Avni Yona
Published: April 2011

The effect of chronic captopril administration on indocyanine green (ICG) clearance and hepatic extraction has been studied in the rat using the intact liver for ICG clearance and the isolated perfused liver for ICG extraction. The captopril was added to the drinking water to give a calculated daily intake from 0–45 mg kg−1. Hepatic clearance of ICG was dose related from 16.5 ± 2.4 (control) to 7.2 ± 1.6 mL min−1. kg−1, respectively. The hepatic extraction of ICG was not significantly different (37 ± 6%) from the control value in groups on 4 and 45 mg kg−1 daily. Since ICG clearance and extraction are dependent on hepatic blood, a change in ICG clearance without a change in the extraction reflects a similar change in the hepatic blood flow. This remained unchanged at daily captopril intakes of 1 and 4 mg kg−1 and decreased when the daily intake was 10 mg kg−1 or higher. If these results in the rat are applicable to man, the chronic administration of therapeutic doses of captopril (0.5-2 mg kg−1) will not affect the hepatic blood flow.
Leukotriene Receptor Antagonism and Augmentation of β-Receptor-mediated Events by LY171883
Authors: Rinkema Lynn E , Roman Carlos R , Russell Weihua L , Spaethe Stephen M , Bemis Kerry G , Henry David P , Marshall Winston S , Fleisch Jerome H
Published: April 2011

LY171883, (1-[2-hydroxy-3-propyl-4-((4(1H-tetrazol-5-yl)butoxy)phenyl]ethanone), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl-xanthine (IBMX) and theophylline, for its ability to augment β-receptormediated responses. Relaxation of carbachol-contracted guinea-pig trachea by isoprenaline was enhanced by the three agents in a dose-dependent manner. A two-fold enhancement of isoprenaline-induced smooth muscle relaxation was produced by 2.5 μM IBMX, 28 μM LY171883, or 140 μM theophylline. Similar concentrations of IBMX or theophylline did not antagonize LTE4-induced tracheal contractions; LY171883 totally inhibited the response and had significant LTE4 receptor antagonist activity even at 10-fold lower concentrations. Antigen-induced release of histamine and LTC4 from guinea-pig lung was reduced by isoprenaline. Prior treatment with LY171883, IBMX, or theophylline did not enhance this action. Isoprenaline reduced histamine-induced bronchospasm in anaesthetized guinea-pigs. LY171883, 30 mg kg−1, or IBMX, 1 mg kg−1, did not affect the isoprenaline-induced decrease in the histamine response. IBMX, 3 mg kg−1, and theophylline, 30 mg kg−1, augmented the isoprenaline-induced bronchodilation. LTE4-induced bronchoconstriction was not affected by IBMX or theophylline whereas LY171883 antagonized this response at doses as low as 3 mg kg−1. Therefore, in both in-vitro and in-vivo test systems, LY171883 functioned primarily as a leukotriene receptor antagonist with minimal pharmacological activity attributable to its ability to potentiate isoprenaline.
Effect of zinc sulphate on acetic acid-induced gastric ulceration in rats
Authors: Li Kong M
Published: April 2011

The effects of zinc sulphate on gastric ulcer healing rate and mucosal mucus content of acetic acid-induced ulceration in rats have been assessed. Daily treatment with zinc sulphate progressively accelerated ulcer healing in a dose-dependent manner with a significant increase observed on day 15 after ulcer induction in rats treated with 44 and 88 mg kg−1 zinc sulphate. A significant increase in gastric mucosal adherent mucus was also observed in those animals treated with 88 mg kg−1 zinc sulphate. The results suggest that a minimum treatment period of 15 days is needed for the zinc sulphate to be effective, and that zinc ions may promote gastric ulcer healing by enhancing mucus formation to prevent acid back-diffusion into the gastric mucosa.
The effect of Fluosol-DA and Hespan haemodilution on S-warfarin elimination in the rat
Authors: Shrewsbury Robert P , Hong Donald D
Published: April 2011

Fluosol and Hespan haemodilution in rats did not change 5-warfarin elimination within 72 h although previous studies had indicated that Fluosol haemodilution caused an increased cytochrome P450b and P450c activity at 48 h. This study showed that the increased activity at that time was specific for those isoenzymes.
Improved method for morphine determination in biological fluids and tissues: rapid, sensitive and selective
Authors: McLean Colin F , Mather Laurence E , Odontiadis John , Sloan Paul A
Published: April 2011

Morphine was assayed using a simple two step solvent extraction—acid back extraction sample preparation method, coupled with normal phase high-performance liquid chromatography (HPLC) and dual electrode coulometric detection. HPLC is performed with a 1.0 M Tris-methanol (5:95) mobile phase with subtle pH adjustments to separate morphine and internal standard from any interfering compounds. The use of normal phase HPLC (silica column) substantially reduces problems from interfering lipophilic substances sometimes encountered with reverse phase HPLC following solvent extraction and which would otherwise require more time-consuming sample preparation. Dual electrode detection further improves the selectivity for morphine and gives excellent sensitivity (0.5 ng mL−1), reproducibility and stability for automated sample injection. This method has proven suitable for pharmacokinetic studies of morphine.
Effects of Fedotozine on Gastrointestinal Motility in Dogs: Mechanism of Action and Related Pharmacokinetics
Authors: Pascaud X , Honde C , Gallou B LE , CHanoine F , Roman F , Bueno L , Junien J L
Published: April 2011

The effects of fedotozine, (+)-(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N- dimethyl-n-propylamine, on motility of the antrum and small intestine were investigated in dog. In fasted dogs, following i.v. administration, fedotozine at 1 and 2 mg kg−1 stimulated and at 5 mg kg−1 inhibited antral motility. Between 1 to 5 mg kg−1, fedotozine exhibited a sustained and potent stimulatory effect on the small intestine inducing 1 to 4 phases III of the migrating motor complex (MMC) lasting up to 32 min in the duodenum and migrating to the jejunum. Following oral administration, fedotozine at 2–5 and 5 mg kg−1 constantly stimulated both antrum and small intestinal motility. In fed dogs, fedotozine i.v. (2 mg kg−1) increased antral motility and induced phase III of MMC in the place of postprandial pattern. Naloxone (0.3 mg kg−1 i.v.) and naloxone methylbromide (2 mg kg−1 i.v.) inhibited the stimulatory effects of fedotozine on gastrointestinal motility indicating a peripheral opiate site of action of the drug whereas phentolamine, hexamethonium, propranolol and methysergide were inactive. In-vitro fedotozine showed submicromolar affinity for opiate receptors with a weak specificity for the μ-receptors in guinea-pig brain and myenteric plexus preparations. Plasma concentrations in dogs receiving fedotozine administered orally at 2.5 mg kg−1 (and in all dogs except one at 5 mg kg−1) were below the detection limit (< 20 ng g−1). In contrast, tissue concentrations in the muscle and mucosal layers of the gut were above 1 μg g−1. Concentrations in gastric juice after i.v. injection of fedotozine were 10 to 20 times higher than in the plasma, indicating passage of the drug from the blood into the lumen. These results indicate that fedotozine between 1 to 5 mg kg−1 orally or i.v. stimulates gastrointestinal motility in dog through peripheral opiate receptors. This peripheral activity is related to a high distribution of the drug at the target organ.
A Pharmacodynamic Model to Predict the Time Dependent Adaptation of Dopaminergic Activity During Constant Concentrations of Haloperidol
Authors: Cheng V F , Paalzow L K
Published: April 2011

The concentration-response relationship of the accumulation of brain homovanillic acid (HVA) has been studied by giving rats a shorter (12 h) and a longer (76 h) constant intravenous infusion of haloperidol, respectively, at rates aiming at different steady state blood concentrations of haloperidol of 5 to 30 ng mL−1. The observed response on brain HVA concentration vs increasing steady state blood concentration of the drug produced a bell-shaped type of curve during the 12 h infusion. When the infusion proceeded for 76 h a similar type of curve was obtained but it was shifted downwards compared with the 12 h infusion. The dopaminergic activity of the rat brain, as reflected by the HVA levels, therefore adapted to a lower activity during the prolonged exposure to haloperidol. To follow the time course of this adaptation, one steady state level of about 12 ng mL−1 was established and kept for 12, 28, 52 and 76 h. The result showed that the accumulation of brain HVA decreased over time compared with control animals given placebo. A pharmacodynamic model was set up to quantitatively describe the time-dependent adaptation of HVA accumulation in the whole rat brain during constant haloperidol administration. By fitting this model to all three sets of experimental data simultaneously, an adaptation half-time of about 38 h ± 14(s.d.) and a tolerance potency of about 7 ng mL−1 were obtained which could be used to calculate that, for example, at a constant blood level of 10 ng mL−1 haloperidol over 5 days the accumulation of brain HVA decreased by approximately 91% of the maximal decrease. Since the therapeutic effects of haloperidol take time to become apparent, the adaptation of HVA-accumulation seen in the present experiments and in the clinical literature could be related to the drug's antipsychotic effect. The adaptation half-time could be a useful parameter to describe and predict the rate of development of the desired therapeutic effect. Furthermore. the observed bell-shaped effect of increasing steady state blood concentrations of haloperidol on the accumulation of brain HVA corresponded to the clinically observed therapeutic haloperidol plasma concentrations of patients with schizophrenia.
Frusemide potentiates acetylcholine and carbachol in contracting the rat urinary bladder
Authors: Okpukpara J N , Akah P A
Published: April 2011

The interaction between acetylcholine and carbachol, and frusemide, a loop diuretic, have been studied on the rat isolated urinary bladder strip preparation. Acetylcholine (4.36 × 10−8–1.3 × 10−6 M) and carbachol (5.5 × 10−8–6.9 × 10−6 M) induced contractions and these were significantly potentiated by frusemide (3.02 × 10−6 M). The ratio of EC50 in the absence of frusemide to EC50 in the presence of frusemide was 1.58 ± 0.03 (s.e.m.) for acetylcholine and 1.86 ± 0.14 for carbachol. Potentiation of acetylcholine and carbachol contractions by frusemide was not observed in tissues treated with hexamethonium (2.5 × 10−5 M). Rhythmic contractions induced by frusemide alone were markedly reduced by hexamethonium (2.5 × 10−5 M) and tetrodotoxin (10−6 M) but they were not significantly reduced by atropine (1.7 × 10−6 M). The result suggests that frusemide increases the sensitivity of the bladder to acetylcholine and carbachol, and that it may have a nicotinic stimulant effect on the bladder. This extra-renal action may contribute to its prompt diuretic property.
Initial and Steady State Pharmacokinetics of Cilazapril in Congestive Cardiac Failure
Authors: Wiseman M N , Elstob J E , Francis R J , Brown A N , Rajaguru S , Steiner J , Dymond D S
Published: April 2011

Twenty one patients with NYHA class II—III congestive heart failure received single ascending doses of 0·5, 1·25 and 2·5 mg cilazapril daily followed by the minimum effective dose for six weeks. Fifteen patients completed the study, but the data from only 11 were sufficiently complete for kinetic evaluation. The pharmacokinetics of the metabolite, cilazaprilat, after a single dose of 0·5 mg cilazapril were similar to previous observations in healthy volunteers at identical dosage. Repeat administration, however, led to greater accumulation than previously observed in volunteers at the higher dosages of 1·25 or 5 mg given for 8 days. Seven patients experienced adverse events. Four were severe, leading to withdrawal of the patients from the study, but only one event was related to cilazapril. Of the other three, one suffered a myocardial infarction and subsequently died due to worsening congestive heart failure. One other patient was withdrawn with two adverse events probably related to cilazapril. No other deaths occurred amongst the study population, and there were no significant abnormalities in haematology or blood chemistry.
Acute Effects of Beclamide on Brain Regional Monoamine Concentrations, their Metabolites and Radioligand Binding Studies
Authors: Darmani N A , Sewell R D E , Nicholls P J
Published: April 2011

The effects of beclamide on regional brain monoamine levels and radioligand binding have been studied in rats. One hour oral pre-treatment with beclamide (400 mg kg−1) increased rat striatal dopamine turnover by increasing the levels of its major metabolites (DOPAC and HVA) three-fold. Simultaneously the drug reduced the concentration of striatal dopamine by a similar factor, and the concentrations of 5-hydroxytryptamine, (5-HT), 5-hydroxyindoleacetic acid, (5-HIAA) and 3-methoxytyramine in the striatum were reduced below the detection limits of the assay. In the frontal cortex, beclamide depleted the dopamine, 5-HT and 5-HIAA content whilst having no significant effect on the noradrenaline level. The concentrations of bioamines and their metabolites in the hypothalamus were unaffected by such acute beclamide treatment. In radioligand binding studies beclamide lacked affinity and failed to displace radioligands from α2, β, 5-HT, 5-HT2 and dopamine D2 sites in selective loci of the rat brain.
H+ coupled transport of orally active cephalosporins lacking an α-amino group across brush-border membrane vesicles from rat small intestine
Authors: Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi
Published: April 2011

The effect of an inwardly directed H+ gradient on the transport characteristics of ceftibuten, cefixime and analogues of ceftibuten in rat intestinal brush-border membrane vesicles have been investigated. In the presence of a transmembrane H+ gradient, ceftibuten and its analogues exhibited a peak to equilibrium overshoot and an accumulation in the vesicles against the concentration gradient. However, the uptake of cefixime and S-1006 [(6R, 7R)-(7-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-8-oxo-3-carba-moyloxy-methyl-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid), which lacks a carboxyl group at position 4 of carboxyethylidene structure, exhibited no overshoot, although the equilibrium uptake was increased by a H+ gradient. The equilibrium uptake was dependent on the pH of the final incubation medium and the H + gradient. These data suggested that the orally active cephalosporins were transported into rat intestinal brush-border membrane by the transmembrane H+ gradient and the pH of the medium.
Subcellular distribution of metformin in rat liver
Authors: Wilcock Carol , Wyre N D , Bailey C J
Published: April 2011

The subcellular localization of metformin was studied in livers of 18 h fasted rats treated orally with [14C]metformin 20 μCi kg−1, 50 mg kg−1. Sequential determination of 14C radioactivity showed that maximum concentrations of metformin in plasma (about 15 μmol L−1) and liver (about 50 μmol kg−1) were achieved at 30–60 min and approximately half-maximal concentrations were achieved at 4 h. At 30 min and 4 h after administration of [14C]metformin, livers were removed and homogenized. Nuclear, mitochondrial and lysosomal, mixed membrane, and cytosolic fractions were separated by ultra-centrifugation. Distribution of 14C was similar at both time points, being greatest in the cytosolic fraction (78% of total radioactivity, and 60–69% of relative specific activity). Small amounts of 14C were associated with the other fractions. The total radioactivity and relative specific activity were respectively 2–3% and 7–8% in the nuclear fraction, 9–10% and 7–10%) in the mitochondrial and lysosomal fraction, and 8–9% and 13–14% in the mixed membrane fraction. The higher concentration of metformin in liver compared with plasma suggests that metformin enters hepatocytes via a specific mechanism, and is distributed mainly within the cytosol.
Microemulsions as topical drug delivery vehicles: in-vitro transdermal studies of a model hydrophilic drug
Authors: Osborne D W , Ward A J I , O'Neill K J
Published: April 2011

Microemulsions with a 58:42 weight ratio of dioctyl sodium sulphosuccinate: octanol and containing 15, 35, and 68% water have been tested for their ability to transport glucose across human cadaver skin. A flow-through multisample skin diffusion cell showed that both the 35 and 68% water microemulsions caused enhanced (approximately 30-fold) transport of glucose. No transport was discernible for the 15% water microemulsion. Differences in percutaneous glucose transport were shown to parallel differences in the diffusion of water within the microemulsion vehicles before application to the skin.
Isomerization of Lactose in Solid-state by Mechanical Stress During Grinding
Authors: Otsuka Makoto , Ohtani Hiro , Kaneniwa Nobuyoshi , Higuchi Shigesada
Published: April 2011

Isomerization during grinding of solid-state α-monohydrate, α-anhydrate and β-anhydrate of lactose was investigated. Samples were ground in an agate centrifugal ball-mill at 270 rev min−1 at room temperature (20°C). The crystallinity of ground lactose was measured by Hermans' method from the powder X-ray diffraction profiles. The α-and β-lactose content of the ground lactose was obtained from the specific rotation measured by using angular rotation spectrophotometry. The crystalline lactose samples were transformed into non-crystalline solids by mechanical stress during grinding. After grinding, the water content of all ground lactose samples increased, and the samples had about 2 mol water per lactose after 10 h grinding. After 10 h grinding of α-monohydrate and α-anhydrate, 10 and 15%, respectively, of α-lactose was transformed into β-lactose by the mechanical treatment. After 10 h grinding of β-lactose, 20% of β-lactose was transformed into α-lactose. The results suggest that crystalline lactose was transformed into a non-crystalline solid, and water was adsorbed on the non-crystalline lactose. The non-crystalline solids of α-or β-lactose were then transformed into their counterparts by the mechanochemical effects of grinding.
Lipid-itraconazole Interaction in Lipid Model Membranes
Authors: Brasseur R , Goormaghtigh E , Ruysschaert J-M , Duquenoy P H , Marichal P , Bossche H Vanden
Published: April 2011

Itraconazole, a lipophilic, fungal sterol-biosynthesis inhibitor, does not disturb membrane organization parameters measured by differential scanning calorimetry and infrared spectroscopy. Conformational analysis studies suggest that the molecular volume and the position of itraconazole in the lipid membrane is similar to that of dipalmitoyl phosphatidylcholine. The mean energy of interaction between itraconazole and the phospholipid is-60.6 kJ mol−1 whereas this energy in the pure lipid matrix is-54.3 kJ mol−1. The mean molecular area of itraconazole calculated by projecting the molecule on the lipid-water interface is equal to that occupied by the pure lipid (60 Å2/molecule).
Analgesic effect of μ-and κ-opioid agonists in beige and CXBK mice
Authors: Muraki Takamura , Oike Nobuko , Shibata Yoshie , Nomoto Teruko
Published: April 2011

The analgesic effects of μ-and κ-opioid agonists, including morphine, FK33,824, U50,488H, tifluadom and bremazocine, have been determined in C57BL/6J-bgJ (beige) and CXBK mice which are hyporesponsive to μ-opioid receptor-mediated analgesia compared with those of control mice (C57BL/6J (C6J), C57BL/6By (C6By), BALB/cBy (BALB)) using an abdominal constriction assay. The analgesic effect of subcutaneously administered morphine and FK33,824 in both beige and CXBK mice was significantly reduced compared with the controls and the analgesic effect of U50,488H and tifluadom in beige mice was significantly reduced compared with the wild strain (C6J). No reduction of analgesic effect of U50,488H and tifluadom was seen in CXBK compared with its progenitor strains, C6By and BALB, except for a reduction of the effect of tifluadom in CXBK compared with C6By. There was no strain difference in the bremazocine-induced analgesia. These results suggest that the beige mouse has a deficit in analgesia mediated by both μ-and κ-opioid receptors, whereas the CXBK is deficient only in the μ-opioid receptor-mediated analgesia.
Effects of Compaction Variables on Porosity and Material Tensile Strength of Convex-faced Aspirin Tablets
Authors: Pitt K G , Newton J M , Stanley P
Published: April 2011

The porosity and tensile strength of convex-faced aspirin tablets formed under a compaction pressure in the range 40–320 MPa and at punch velocities in the range 0.008 to 500 mm s−1 have been determined. The material tensile strength, σf, was calculated from the observed fracture load, Ps, using the equation of Pitt et al (1988): σf=10PsπD2(2⋅84tD−0⋅126tW+3⋅15WD+0⋅01)−1 where D is the tablet diameter, t is the overall tablet thickness and W is the central cylinder thickness. Tablets formed at lower compaction pressures had a higher porosity and lower tensile strength than those formed at higher compaction pressures. Tablets of face curvature ratio (D/R) in the range 0.25-0.67 and a normalized cylinder length (W/D) of 0.2 had the optimum tensile strength. (R is the radius of curvature of the tablet face.) Tablets formed at high compaction rates were significantly weaker than those formed at lower compaction rates.
Percutaneous Absorption of Indomethacin from Transparent Oil/Water Gels in Rabbits
Authors: De Vos F , De Muynck C , Geerts M , Remon J P
Published: April 2011

The percutaneous absorption of indomethacin from transparent oil in water gels (TOW gels) has been studied in rabbits and compared with absorption from a hydrophilic gel and from a spray formulation. The area under the curve and the Cmax values in plasma were significantly higher for the TOW gels in comparison with the other formulations after single application. The pH of the aqueous phase of the TOW gels did not significantly influence the bioavailability. After multiple application the TOW gels induced a larger increase in AUC (vs first application) in comparison with the other formulations. None of the formulations without drug damaged the skin after multiple application. For indomethacin formulations skin damage was more pronounced with the hydrophilic gel than for the TOW gels and spray formulation.
Leucine Modulates Peptide Transport System-1 Across the Blood-brain Barrier at a Stereospecific Site within the Central Nervous System
Authors: Banks William A , Kastin Abba J
Published: April 2011

Previous results have shown that leucine injected into a cerebral ventricle (i.c.v.) can act as an allosteric regulator of peptide transport system-1 (PTS-1), the system that transports Tyr-Pro-Leu-Gly-NH2 (Tyr-MIF-1) and the enkephalins out of the central nervous system (CNS). D-Leucine appeared more potent than L-leucine. In the current study, dose-response curves were constructed for each compound after both intravenous (i.v.) and i.c.v. injection. Based on ED50 values after i.c.v. injection, D-leucine was about 200 times more potent than L-leucine in its inhibition of PTS-1, thereby confirming stereospecificity of the allosteric site, D-and L-Leucine were also more potent when given i.c.v. than when given i.v., suggesting that the site is located on the CNS side of the blood-brain barrier (BBB). The finding that D-leucine was less potent than L-leucine when given i.v. is also consistent with a CNS site of action because the L-isomer of leucine has been shown to be preferentially transported into the brain. These findings agree with the previous suggestion that some of the neurotoxic effects of leucine may be mediated through PTS-1 and could help explain how D-amino acids can exert opiate-related effects on the CNS.
A fluorescence method for the determination of the molecular weight cut-off of alginate-polylysine microcapsules
Authors: Vandenbossche Geert M R , Van Oostveldt Patric , Remon Jean Paul
Published: April 2011

Several applications of microcapsules for the encapsulation of living cells or macromolecules require well defined pore sizes. The molecular weight cut-off of alginate-polylysine microcapsules has been determined using a range of fluorescent labelled dextran molecules. The diffusion of the fluorescein isothiocyanate labelled (FITC)-dextrans into the microcapsules was followed by fluorescence and confocal laser scanning microscopy. The permeability of microcapsules for FITC-dextrans with a molecular weight of 4 700 daltons and the impermeability for FITC-dextrans with a molecular weight of 40 500 daltons was confirmed with both techniques. Determination of the molecular weight cut-off, using confocal laser scanning microscopy was more reliable and required a smaller sample than fluorescence measurements.
Unusual solubility behaviour of cyclosporin A in aqueous media
Authors: Ismailos George , Reppas Christos , Dressman Jennifer B , Macheras Panayotis
Published: April 2011

The solubility of cyclosporin A was determined in water and in Sorensen buffers at pH 1.2 and 6.6 at temperatures ranging from 5 to 37°C. No differences in solubility behaviour were observed among the three aqueous media. Solubility was found to be inversely proportional to the temperature in each medium, indicating that the heat of solution was exothermic in each case.
The inhibitory action of zinc sulphate on the contractile activity of guinea-pig ileum
Authors: Cho C H , Teh G W
Published: April 2011

The present study examines the inhibitory action of zinc sulphate (ZnSO4) on the contractile response of various agonists on guinea-pig isolated ileum. Different doses of agonists were selected to produce similar contractile activity, in order to compare the degree of inhibition produced by ZnSO4 Preincubation of ileum with ZnSO4 1 × 10−3 or 3 × 10−3 M for 10 min dose-dependently and significantly prevented the contraction induced by acetylcholine (1.7 × 10−8 M), 5-HT (2.4 × 10−6 M), histamine (5.4 × 10−7 M) and nicotine (1.7 × 10−6 M) but not by prostaglandin E2 (PGE2, 8.5 × 10−9 M). The same doses of ZnSO4 reduced the twitch contraction produced by electrical field stimulation. These findings indicate that the contractile activity of PGE2 is mediated by a mechanism different from that of other agonists and of electrical field stimulation. It is likely that the contractile activity of PGE2 is acting through the receptors on the ileal muscle which are not blocked by ZnSO4 pretreatment.
A comparison of aminopeptidases from excised human buccal epithelium and primary cultures of hamster pouch buccal epithelium
Authors: Audus Kenneth L , Williams Amos , Tavakoli-Saberi M Reza
Published: April 2011

Aminopeptidase activity associated with human buccal tissue and primary cultures of hamster buccal epithelium homogenates was assayed fluorometrically using 4-methoxy-2-naphthyl-amides of leucine, alanine, and arginine. Kinetic parameters, Km and Vmax. for all substrates were estimated. Aminopeptidase parameters for human tissue were similar to those for the in-vitro system and reported literature values for rodent buccal tissue aminopeptidases. Aminopeptidases of both tissues were also found to be similarly sensitive to typical inhibitors, bestatin and puromycin. Overall results suggest that appropriate in-vitro systems derived from animal tissues may be useful in assessing the role and localization of peptidases associated with buccal tissue.
The effect of nitrous oxide on S-adenosylmethionine levels in mouse brain
Authors: Dorris Roy L
Published: April 2011

Mice were exposed to nitrous oxide (50%) for up to 24 h and S-adenosylmethionine (SAMe) levels measured in corpus striatum and cerebellum, areas with high and low catecholamine turnover rates, respectively. After 4 h, levels were 21 and 8% and after 6 h, 33 and 14% lower than controls in striatum and cerebellum, respectively. Thus, the effect was more pronounced in corpus striatum, the area with the presumed higher rate of catecholamine O-methylation. With continued exposure to nitrous oxide SAMe concentrations in the two areas returned to nearly normal at 24 h. The observation that levels did not continue to decline, and even returned towards control levels, while animals were still in the presence of the gas suggests that a mechanism other than that of methionine synthase inhibition may have been responsible for the initial effect. Alternatively, some other source of SAMe may have become available to compensate for the inhibition of the enzyme.
α1-Adrenoceptor Subtypes in the Rat Ventricular Muscle
Authors: Kinami Junji , Tsuchihashi Hiroshi , Baba Shoko , Mano Fumie , Maruyama Keiko , Nagatomo Takafumi
Published: April 2011

Scatchard analyses of [3H]prazosin binding in rat ventricular muscle membranes showed biphasic curves, which identified α1High- and α1Low-affinity sites. The α1High-affinity site was completely inhibited by 1 μm phenoxybenzamine. The displacement potencies of α1-adrenergic antagonists were characterized by [3H]prazosin binding to α1High. and α1Low-affinity sites in the absence and presence of 1 μm phenoxybenzamine. The affinities of most chemicals for α1Low-affinity sites were significantly lower than those for α1High-affinity sites, but WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane), arotinolol, cinanserin, nifedipine, and p-aminoclonidine had the same affinities for both α1Low- and α1High-affinity sites. These results show that two α1-adrenoceptor subtypes, α1High- and α1Low-affinity, are present in the rat heart, and that there are physical variations in α1-adrenoceptor binding sites, based on their selectivity to antagonists.
Absorption kinetics of cyclosporin in the rat
Authors: Hedayati Shahram , Bernareggi Alberto , Rowland Malcolm
Published: April 2011

Cyclosporin was administered (6 mg kg−1, i.v.) over 15 min, or (10 mg kg−1) by gavage, to two groups of 5 rats. Following i.v. infusion, cyclosporin exhibited triphasic behaviour with mean ± s.e.m. disposition half-lives of 9·0 ± 1·3 min, 4·0 ± 0·5 h and 16·0 ± 1·7 h. Following oral administration, peak blood concentration (Cmax) of 1290 ± 93 ng mL−1 was reached after 5 h, when cyclosporin absorption essentially ceased. The absolute bioavailability (F) of cyclosporin was 24·0%. Standard laboratory rat chow consisting of 2% corn oil did not appear to alter cyclosporin absorption kinetics.
Supersensitivity of isolated atria from diabetic rats to adenosine and methacholine: modulation by pertussis toxin
Authors: Li Xiao-Jiang
Published: April 2011

The chronotropic response of isolated right atria obtained from rats made diabetic 14–15 weeks previously by streptozotocin, was compared with age-matched controls. Diabetic rat atria are significantly more sensitive to the negative chronotropic actions of adenosine and of methacholine. Pretreating both control and diabetic rats with 2·5 mg kg−1 pertussis toxin attenuated the negative chronotropic effects of methacholine and adenosine on isolated atria, although diabetic atria still displayed a significantly greater sensitivity to these agonists (P < 0·05–0·001). The negative chronotropic effects of methacholine and adenosine on both control and diabetic atria were abolished following pretreatment with higher doses of pertussis toxin (10 mg kg−1). These results suggest that pertussis toxin-sensitive G proteins may be involved in the supersensitivity of diabetic hearts to methacholine and adenosine.
A Possible Mechanism of Endothelium-dependent Relaxation Induced by Pirarubicin and Carbachol in Rat Isolated Aorta
Authors: Hirano Shin-Ichi , Agata Naoki , Hara Yutaka , Iguchi Hiroshi , Shirai Masataka , Tone Hiroshi , Urakawa Norimoto
Published: April 2011

The mechanism of endothelium-dependent relaxation induced by pirarubicin, (2″R)-4′-O-tetrahydropyranyladriamycin, THP, or carbachol was investigated in the rat isolated aorta. The relaxant effect of THP (1·5 × 10−6-4·5 × 10−5  m) or carbachol (10−8-10−4  m) on the aorta with endothelium was decreased by lowering Ca2+ in the medium. The relaxation induced by THP was not inhibited by pretreatment with verapamil (10−6–10−5  m), and that induced by carbachol was only partially inhibited. However, on replacement of all but 20 Mm Na+ with either Li+ or choline, the THP- or carbachol-induced relaxation was inhibited. Furthermore, the relaxing effect of THP or carbachol was inhibited by pretreatment with amiloride (10−4-3 × 10−4  m), with ouabain (10−4-10−3  m), or with K+-depletion. These results suggest that the THP- or carbachol-induced relaxation depending on endothelium was affected by modifying the calcium ion concentration, and that a Na+–Ca2+ exchange process is involved.