bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased ex-vivo colonic generation of PAF induced by diphenylmethane stimulant laxatives in rats, mice, guinea-pigs and rabbits
Authors: Izzo A A , Mascolo N , Autore G , Di Carlo G , Capasso F
Published: April 2011

The effects of in-vivo treatment with bisacodyl, phenolphthalein, picosulphate, sulphosuccinate, mannitol and lactulose laxatives were examined on the ex-vivo formation of platelet-activating factor (PAF) by duodenum and colon of rat, mouse, guinea-pig and rabbit. Bisacodyl (10 mg kg−1), phenolphthalein (20 mg kg−1) and picosulphate (10 mg hg−1), but not sulphosuccinate (40 mg kg−1), mannitol (50 mg kg−1) or lactulose (50 mg kg−1), at doses that all caused laxation, markedly increased PAF in the colon (P < 0·01) but not in the duodenum. Intraluminal release of acid phosphatase was also significantly increased in the colon of rats treated with bisacodyl, phenolphthalein and picosulphate, but not in colons of animals treated with sulphosuccinate, mannitol or lactulose. The data show that enhanced generation of PAF is associated with the colonic damage induced by diphenylmethane laxatives, but do not show whether this is a cause or a consequence of the pathophysiological changes.
Ciliotoxicity of methyl- and propyl-p-hydroxybenzoates: a dose-response and surface-response study
Authors: Jian L , Po A Li Wan
Published: April 2011

The effect of methyl-p-hydroxybenzoate (methyl para-ben, MHB) and propyl-p-hydroxybenzoate (propyl paraben, PHB) on ciliary beat frequency was investigated using surface-response methodology. Both compounds are shown to be ciliotoxic at concentrations equal to or lower than those in use for preserving aqueous formulations. The dose-response curves show the typical sigmoidal pattern. Interaction by the two compounds is evidenced by the curved response surface for ciliotoxicity.
Emulsified Perfluorochemicals as Respiratory Gas Carriers: Recovery of Perfluorodecalin Emulsion Droplets from Rat Tissues
Authors: Lowe K C , Washington C
Published: April 2011

To further understand the in-vivo biokinetic behaviour of perfluorochemical (PFC) emulsions, male rats were injected (10 mL kg−1) with 30% (w/v) emulsified perfluorodecalin (FDC) and uptake into tissues assessed. At 72 h after injection, the mean (±s.e.m.) diameters of FDC droplets recovered from liver and spleen were 2·24 ± 0·04 and 2·78 ±0·10 μm, respectively; droplets recovered from lung after 72 h (mean: 1·73 ±0·13 μm) were significantly smaller (p < 0·01). After 7 days, FDC droplet diameters in liver had increased to 3·31 ± 0·13 μm (P < 0·01) and those in lung to 2·71 ± 0·14 μm (P < 0·01); droplets in spleen after 7 days (2·22 ± 0·09 μm) were similar to those at 72 h. These data support the hypothesis that significant initial coalescence of FDC droplets occurs in the rat liver and spleen, with further coalescence in the liver up to 7 days. The mean percentage of the injected FDC dose recovered from the liver after 72 h was 2·2 ± 0·4%, and after 7 days was 0·07 + 0·05% (P < 0·01). A smaller decrease in the percent injected FDC in spleen also occurred over the same period (72 h: 1·9 ± 0·3%; 7 days: 0·8 ± 0·5%; P < 0·01). The percent injected FDC in lung was similar at 72 h (0·007 ± 0·004%) and 7 days (0·005 ±0·001 %). FDC was undetectable (< 0·001 %) in all blood samples. The greater rate of FDC elimination from the liver than from the spleen may be related to differences in the rates of reticuloendothelial system processing between these organs.
Effect of an Histaminergic H3 Agonist on the Non-adrenergic Non-cholinergic Contraction in Guinea-pig Perfused Bronchioles
Authors: Burgaud J L , Oudart N
Published: April 2011

From the bronchioles of guinea-pigs, preparations were isolated for registration of perfused pressure on electrical field stimulation (EFS) and by application of drugs. The perfused bronchioles contracted when EFS was applied in the presence of atropine and phentolamine suggesting a non-adrenergic non-cholinergic (NANC) response. (R)-α-Methylhistamine (methylhistamine), a selective H3 agonist, reduced the NANC bronchoconstrictor response in a concentration-dependent manner. β-Adrenoceptors, muscarinic and histamine (H1) and H2 receptor) antagonists, epithelial removal and cyclooxygenase inhibition had no effect on this inhibitory action of methylhistamine whereas the H3 antagonist, thioperamide, reduced the inhibitory effect of methylhistamine with a Ki value of 2·98 × 10−9  m. Methylhistamine had no effect on the concentration-dependent contraction induced by exogenous substance P and neurokinin A, demonstrating that an H3 receptor might inhibit the release of transmitter from NANC nerves on guinea-pig perfused bronchioles in-vitro.
Effect of Fepradinol on Rat Hind Paw Oedema Induced by Several Inflammatory Agents
Authors: Masso J M , Conde J R , Villar A M , Martorell J
Published: April 2011

Fepradinol is an effective non-steroidal anti-inflammatory agent. The effect on rat paw oedema induced by various phlogistic agents was investigated. The inhibitory effect of fepradinol (25 mg kg−1, p.o.) on dextran-induced oedema was nearly equal to that of cyproheptadine (10 mg kg−1, p.o.). On oedema induced by platelet-activating factor only fepradinol (25 mg kg−1, p.o.) and phenidone (100 mg kg−1, p.o.) clearly inhibited the inflammatory process. Both the above induced oedemas are thought to be unrelated to prostaglandins in the rat system and therefore, the anti-inflammatory activity against them is not shared by selective cyclo-oxygenase inhibitors. Fepradinol (25 mg kg−1, p.o.) displayed an inhibitory effect on the early and late stage of kaolin- and nystatin-induced oedemas in contrast with indomethacin (10 mg kg−1, p.o.) and piroxicam (10 mg kg−1, p.o.) which only inhibited the late stage. The results obtained in this study confirm that fepradinol is a potent anti-inflammatory agent and indicate that its mechanism of action is different from that of other anti-inflammatory compounds.
Incorporation of alphaxalone into different types of liposomes
Authors: Dean T P , Hider R C
Published: April 2011

The poor solubility of steroid anaesthetics in water has been a serious drawback in the development of clinically acceptable intravenous formulations. The use of Cremophor EL to solubilize steroids such as alphaxalone led to unacceptable hypersensitivity reactions and consequent withdrawal of this anaesthetic. In principle, liposomes can act as a safe solvent for the intravenous administration of alphaxalone. We report the incorporation of [14C]acetylated alphaxalone in both multilamellar vesicles and stable plurilamellar vesicles prepared from a range of amphiphiles including synthetic polyhydroxyl lipids. For both types of preparations, addition of cholesterol to phosphatidylcholine-based lipids caused an increase in encapsulation efficiency. Maximum encapsulation was achieved with the stable plurilamellar vesicle preparation of 1-stearyl-2-myristylglycerate-3, N-methylglucamine: cholesterol: egg phosphatidylcholine (78%). The rate of efflux of this anaesthetic from a range of liposomes was measured in serum. The highest rate (85% after 30 min) was observed with an equimolar egg phosphatidylcholine: cholesterol stable plurilamellar vesicle preparation. From these studies it can be concluded that liposomes offer a suitable alternative for intravenous delivery of steroidal anaesthetics.
Calorimetric study on the solubilization of butanol by alkylphosphate and alkylphosphate-lecithin systems
Authors: Trotta M , Fubini B , Gallarate M , Gasco M R
Published: April 2011

Microcalorimetric studies on alkylphosphate-butanol and alkylphosphate-butanol-lecithin systems were carried out as a first step to study the role of butanol (used as cosurfactant) in the formation of microemulsions. The enthalpy of solubilization: ΔH, of the same amount of butanol (1·806 mol kg−1) in aqueous sodium monoalkyl-phosphates, with a hydrocarbon chain varying from 6 to 10 carbon atoms, was investigated as a function of alkylphosphate concentration. Measurements were performed in the presence and in the absence of lecithin. The enthalpy values measured upon addition of butanol to the mixtures were negative in all cases. Below the critical micelle concentration (CMC) of the alkylphosphates, the heats of butanol dissolution were found to decrease upon increasing the concentration of the alkylphosphate. This behaviour was related to the dissolution of butanol in water and to the formation of mixed butanol-alkylphosphate and butanol-alkylphosphate-lecithin micelles. Above the CMC essentially constant ΔH values were found. The ΔH measured may be the sum of simultaneous effects—heat of alcohol dissolution and the simple alkylphosphate micelle dissociation or alkylphosphate-lecithin mixed aggregate dissociation and the heat of mixed micelle formation. The ΔH at the plateaus were linearly related to the corresponding CMC values of the alkylphosphates.
The effect of a nutritional model of chronic liver injury on the hepatic glucuronidation of morphine in rats
Authors: Callaghan Richard , Desmond Paul V , Masheord Maurice L
Published: April 2011

The effect of a choline-deficient diet on the hepatic glucuronidation of morphine was investigated using a rat perfused liver system. Rats fed a choline-deficient diet developed a fatty liver with minimal necrosis. Despite the morphological changes, neither hepatic extraction ratio (0·51 ± 0·02 incontrol; 0·45 ± 0·04 in the choline-deficient rats) nor intrinsic clearance (0·85 ± 0·05 in control; 0·77 ± 0·09 in choline-deficient rats) were affected by this injury model. This finding suggests that glucuronidation is relatively resistant to this chronic liver injury.
An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate
Authors: Subarnas Anas , Tadano Takeshi , Kisara Kensuke , Ohizumi Yasushi
Published: April 2011

Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg−1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg−1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg−1, i.p.), but was potentiated by prazosin (0·75 mg kg−1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg−1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg−1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α1-adrenoceptors.
Rheology of Model Aerosol Suspensions
Authors: Sidhu B K , Washington C , Davis S S , Purewal T S
Published: April 2011

The rheological properties of model aerosol suspensions at phase fractions of less than 5% w/v (phase ratio of 0.05) were investigated. The rheological profiles of lactose in chloroform, lactose in trichlorofluoromethane (Propellent 11, P11), and salbutamol sulphate in P11 have been investigated in the presence and absence of lecithin, a phospholipid surface-active agent. The relative viscosities of these disperse systems correlated with the increasing disperse phase fractions and the addition of surfactant was found to reduce these viscosities to a relative viscosity of aproximately 1·0. The results suggest that the relative viscosity is a useful indicator of flocculation in these systems, and may be valuable in formulation development.
Partition of Dopamine Antagonists into Synthetic Lipid Bilayers: the Effect of Membrane Structure and Composition
Authors: Sarmento Ana Bela , De Lima M C Pedroso , Olivejra C R
Published: April 2011

Partition coefficients, Kp, of four dopamine antagonists (pimozide, fluspirilene, haloperidol and domperidone) between the aqueous phase and lipid bilayer vesicles were determined as a function of lipid chain length, unsaturation and temperature encompassing the range of the lipid phase transition. Model membranes of egg phosphatidylcholine (PC), dimyristoyl (DMPC)-, dipalmitoyl (DPPC)-, distearoyl (DSPC)- and dioleoyl (DOPC)-phosphatidylcholines were studied. Kp values of the drugs are different in the various membranes under study and depend on temperature, aliphatic carbon chain-length and on the presence of unsaturation in the aliphatic lipid chain. First-order transition of membrane lipids from the gel to the liquid crystalline state is accompanied by a sharp increase of the partition coefficient of pimozide and fluspirilene in DMPC, DPPC and DSPC bilayers. For domperidone, Kp values are maximal within the midpoint of phase transition of DMPC and DPPC, while for DSPC Kp values increase progressively with increasing temperature. Haloperidol Kp values display a maximum at the mid-point of phase transition of DMPC, while a progressive increase of Kp is observed in DPPC and DSPC. The four drugs are easily accommodated in bilayers of short aliphatic chain lipids (DMPC), the partition coefficients being 17137 for pimozide, 18 700 for fluspirilene, 686 for domperidone and 722 for haloperidol, at temperatures 10°C below the mid-point of the lipid phase transition. Except for haloperidol, the partition of the drugs in DOPC (18:1) is higher than that in DSPC (18:0) bilayers at a temperature above the phase transition temperature of both lipids. From our experiments we can conclude that artificial membranes are useful models to understand the physicochemical mechanisms involved in the interaction of dopamine antagonists with biological membranes.
Effect of Local Anaesthetics on the Stimulus-secretion Coupling in Bovine Adrenal Chromaffin Cells
Authors: Kawabata Kazunaga , Sumikawa Koji , Kamibayashi Takahiko , Fukumitsu Kazuo , Hayashi Yukio , Takada Koji , Yoshiya Ikuto
Published: April 2011

This study was carried out to determine the relative potencies of local anaesthetics to inhibit the cholinergic synaptic transmission using cultured bovine adrenal chromaffin cells, and to clarify if the inhibitory action would correlate with biophysical and pharmacological properties. Local anaesthetics (bupivacaine, etidocaine, tetracaine, lignocaine and procaine; 0·02–2 Mm) inhibited carbachol-induced catecholamine release from the cells in a concentration-dependent manner. This inhibition was completely reversible. IC50 (concentration of 50% inhibition) of each anaesthetic showed no correlation with the lipid solubility. The local anaesthetics showed greater inhibitory potency at a higher extracellular pH. The results suggest that clinically relevant concentrations of local anaesthetics inhibit the stimulus-secretion coupling in the chromaffin cells. The un-ionized base form plays a major role, and the inhibitory potency does not depend on the lipid solubility of the anaesthetics.
Buprenorphine-cocaine Interactions in Mice: Effect on Locomotor Activity and Hole-dipping Behaviour
Authors: Jackson Helen C , Griffin Ian J , Nutt David J
Published: April 2011

The effect of cocaine and the mixed μ-opioid partial agonist/κ-antagonist buprenorphine on locomotor activity and hole-dipping behaviour was investigated in mice. The drugs were given alone and in combination. Cocaine (7·5, 15, 30 mg kg−1, i.p.) significantly increased locomotion in a dose-related manner in the hour following injection. The two highest doses also increased hole-dipping although this response was not consistently seen. Buprenorphine (0·5, 5 mg kg−1, i.p.) produced an increase in locomotion which occurred 30–60 min after injection but did not alter hole-dipping behaviour. A lower dose (0·05 mg kg−1) had no effect on either parameter. The locomotion induced by cocaine (15 mg kg−1, i.p.) was not modified by buprenorphine (0·05, 0·5, 1, 5 mg kg−1, i.p.; 5 min pretreatment). However, hole-dipping was almost completely abolished in animals given combinations of cocaine and buprenorphine (0·05–5 mg kg−1, i.p.), although neither drug decreased hole-dipping when given alone. This observation, which was not simply due to the emergence of stereotyped behaviour, suggests an interaction between buprenorphine and cocaine.
Adenosine Stimulates Human Sperm Motility via A2 Receptors
Authors: Shen Meng-Ru , Linden Joel , Chiang Po-Hui , Chen Shun-Sheng , Wu Sheng-Nan
Published: April 2011

The effects of adenosine and its analogues on human sperm motility were studied using a transmembrane migration method. Specific binding sites for adenosine in human sperm were also investigated. Adenosine and 5′-N-ethylcarboxamidoadenosine (NECA) stimulated human sperm motility with similar efficacies and the maximal amplitudes of motility increases were both about 70%. 3,7-Dimethyl-1-propargylxanthine (DMPX), a potent A2 antagonist, competitively antagonized NECA-induced motility stimulation. Successively higher concentrations of DMPX shifted the dose-response curve of NECA to the right in a nearly parallel fashion. Dipyridamole, an inhibitor of adenosine uptake, does not reduce the ability of adenosine to stimulate human sperm motility. In radioligand-binding studies, adenosine A1 selective analogues, cyclopentyl-1,3-dipropylxanthine and 1-methyl-2-phenylethyl adenosine, have little competitive effect on [3H]NECA binding in human sperm membrane. These results provide evidence that adenosine enhances human sperm motility via adenosine A2 receptors on the surface of sperm membranes.
The Effects of Antibiotics and Steroids on the Carriage of Vaginal Bacteria into the Uterus During Insertion of Intra-uterine Monofilaments in the Guinea-pig
Authors: Malhi Jaspal S , Gard Paul R , Hanlon Geoffrey W
Published: April 2011

The effects of systemic norethisterone acetate and oxytetracycline hydrochloride on the levels of vaginal microorganisms found in the uterus after the insertion of transcervical, intra-uterine monofilaments in the guinea-pig were determined. The results indicated that bacteria were transferred to the uterus from the vagina during the insertion process and, in the presence of an intra-uterine substrate, persisted for up to 6 months. Daily treatment with norethisterone acetate or oxytetracycline hydrochloride whilst the monofilament was in-situ failed to reduce the bacterial numbers in the uterus. Similarly, daily treatment with oxytetracycline hydrochloride for the 5 days before monofilament insertion had no effect on these bacteria.
Elucidation of the structural requirements for the bioactivation of mianserin in-vitro
Authors: Roberts P , Kitteringham N R , Park B K
Published: April 2011

The aim of this study was to investigate structure-activity relationships among a series of compounds related to the antidepressant drug, mianserin, with respect to their ability to produce cytotoxic metabolites. Human peripheral lymphocytes were used as target cells and these were exposed to the individual compounds, in the presence or absence of a drug metabolizing system derived from human liver. The individual enantiomers of mianserin showed differences in their cytotoxicity profiles; the R-(–) isomer giving NADPH-dependent cytotoxicity while the S-(+) isomer showed direct cytotoxicity at high concentrations. Cytotoxicity was reduced by removal from mianserin of the nitrogen atom at the 5 position and by substitution of a methyl group for a hydrogen atom at position 14b. In contrast, insertion of an oxygen atom at position 10 of the drug molecule, precluding the formation of a carbonium ion, had little effect on cytotoxic metabolite formation. The data are consistent with the proposal that one or more iminium ions derived from mianserin are responsible for the cytotoxicity observed in this in-vitro system and that appropriate chemical modification may preclude bioactivation of mianserin by P450 enzymes.
Stabilization of thymopentin and preservation of its pharmacological properties by 2-hydroxypropyl-β-cyclodextrin
Authors: Brown Nesbitt D , Butler Dennis L , Chiang Peter K
Published: April 2011

Thymopentin prepared in 5, 15, and 20% 2-hydroxypropyl-β-cyclodextrin (HPCD) was able to inhibit guinea-pig ileum contraction stimulated by anatoxin-a (3 × 10−6  m) after fourteen months of storage at room temperature. Thus, in contrast to the instability of thymopentin prepared without HPCD, the pharmacological activity was retained and could be stored in a ready-to-use solution for extended periods without refrigeration.
Opioid pathways exert a tonic restraint in the guinea-pig isolated colon: changes after chronic sympathetic denervation
Authors: Marino Franca , Creta Filomena , De Ponti Fabrizio , Giaroni Cristina , Lecchini Sergio , Frigo Gian Mario
Published: April 2011

We have studied the effects of naloxone on acetylcholine and noradrenaline release in the guinea-pig isolated distal colon, and have assessed the effect of naloxone on electrically-induced contractions of the longitudinal muscle and non-adrenergic, non-cholinergic (NANC) relaxations of the circular muscle coat. Naloxone dose-dependently increased resting and electrically-evoked acetylcholine release and electrically-evoked noradrenaline release. Naloxone was more potent in increasing resting acetylcholine release in colonic specimens obtained after chronic sympathetic denervation. Naloxone (1 μm) did not affect electrically-induced contractions of the longitudinal muscle, while it enhanced NANC relaxations of the circular muscle. The effects observed with naloxone in the present experiments suggest that opioid pathways exert a tonic restraint on neurotransmission in the guinea-pig colon. After suppression of the adrenergic inhibitory tone, the functional relevance of opioid pathways seems to be increased.
Sequential changes of [3H]cyclic AMP binding in the gerbil brain following transient cerebral ischaemia
Authors: Araki Tsutomu , Kato Hiroyuki , Kanai Yasuo , Kogure Kyuya
Published: April 2011

Sequential alterations in the binding of [3H]cyclic AMP (cAMP) as an indicator of cAMP-dependent protein kinase (cAMP-DPK) binding activity following transient cerebral ischaemia were studied in the gerbil brain using receptor autoradiography. Transient ischaemia was induced for 10 min. [3H]cAMP binding in the stratum oriens and pyramidale of the hippocampal CA1 sector significantly decreased in the early post-ischaemic stage and showed severe reduction 7 days and 1 month after recirculation. By contrast, [3H]cAMP binding showed no significant alterations in the stratum radiatum of the hippocampal CA1 sector and the stratum pyramidale of the hippocampal CA3 sector up to 48 h after ischaemia. However, the binding in these areas significantly decreased 7 days and 1 month after ischaemia. The stratum lacunosum-moleculare of the hippocampal CA1 sector and dentate gyrus showed no significant changes in [3H]cAMP binding throughout the recirculation period. However, in the dorsolateral part of the striatum, where severe neuronal damage was seen morphologically, [3H]cAMP binding was significantly reduced only one month after ischaemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 sector, but not in the striatum. Furthermore, our autoradiographic data suggest that post-ischaemic alteration in [3H]cAMP binding between the hippocampal CA1 sector and striatum may be produced by different mechanisms.
Drug Dissolution from Indomethacin-starch Hybrid Powders Prepared by the Dry Impact Blending Method
Authors: Ishizaka Takafumi , Honda Hirotaka , Koishi Masumi
Published: April 2011

Indomethacin was hybridized with potato starch using a dry impact blending method. Resultant hybrid powders were investigated by scanning electron microscopy and X-ray powder diffraction. Amorphous indomethacin spread over the starch surface in a layer immediately after being hybridized, and then gradually reverted to fine crystalline particles adhering firmly to the starch surface. Indomethacin dissolution from the hybrid powder was compared with those from physical mixtures and granules taken from a commercially available capsule. Indomethacin dissolution from powder and capsule dosage forms, even in an acidic medium, was drastically accelerated by the hybridization.
Further Evaluation of a New Penetration Enhancer, HPE-101
Authors: Yano Tadanori , Higo Naruhito , Fukuda Kazuya , Tsuji Masayoshi , Noda Kanji , Otagiri Masaki
Published: April 2011

The penetration enhancer, 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101), significantly enhanced the excretion of topically applied [14C]indomethacin when dissolved in dipropylene glycol, triethylene glycol, diethylene glycol, 1,3-butylene glycol, trimethylene glycol, glycerin, water, silicone or triethanolamine, but not when dissolved in ethanol, isopropyl alcohol, oleyl alcohol, olive oil, peppermint oil, isopropyl myristate or hexylene glycol. HPE-101 significantly enhanced the excretion of [14C]indomethacin, [14C]nicotinic acid, [14C]5-fluorouracil, [3H]oestradiol and [3H]triamcinolone acetonide, but not that of [3H]testosterone. HPE-101 also significantly enhanced the excretion of [14C]indomethacin applied to intact skin of rabbit, guinea-pig and rat, and to tape-stripped skin of guinea-pig, but did not enhance the excretion of [14C]indomethacin applied to tape-stripped skin of rat or rabbit.
Further Studies on α2-Adrenoceptor Subtypes Involved in the Modulation of [3H]Noradrenaline and [3H]5-Hydroxytryptamine Release from Rat Brain Cortex Synaptosomes
Authors: Gobbi M , Frittoli E , Mennini T
Published: April 2011

Three selective α2A- or α2B-adrenergic antagonists (BRL-44408, BRL-41992 and imiloxan) were cused in the present study designed to classify the presynaptic α2-auto- and heteroreceptors in the rat brain cortex. The rank order of potency in antagonizing the inhibitory effect of (–)-noradrenaline or clonidine on the K+-induced [3H]noradrenaline and [3H]5-hydroxytryptamine (5-HT) release from superfused synaptosomes was BRL-44408 ≥ BRL-41992»imiloxan. The same rank order was found for the affinities of these compounds for [3H]yohimbine binding in human platelet membranes, containing only α2A-adrenoceptors, but does not correlate with the known affinities for α2B-adrenoceptors (BRL-41992 ≥ imiloxan > BRL-44408). These data support the conclusion that presynaptic α2-auto- and heteroreceptors in rat brain cortex do not belong to the α2B-subtype and suggest that the modulation of noradrenaline and 5-HT release may be mediated by the α2A-subtype.
Pharmacokinetics of Chlorimipramine, Chlorpromazine and their N-Dealkylated Metabolites in Plasma of Healthy Volunteers After a Single Oral Dose of the Parent Compounds
Authors: Corte L Della , Valoti M , Palmi M , Giovannini M G , Sgaragli G P
Published: April 2011

A single oral dose of 0·7 mg kg−1 clorimipramine (n= 18) and chlorpromazine (n= 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration-time curve (AUC 0–24) for parent drug plus metabolites 5-fold higher than that observed in the same subjects following chlorpromazine intake (600 ± 87 and 124 ± 14 ng mL−1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43·8 ng mL−1, an average of 3·4 h after dosage, whereas the mean peak chlorpromazine level was 15·1 ng mL−1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate-limited and those of chlorpromazine appeared to be formation-rate-limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment.
Pharmacokinetic and Pharmacodynamic Aspects of Artelinic Acid in Rodents
Authors: Titulaer H A C , Eling W M C , Zuidema J
Published: April 2011

The efficacy of artelinic acid and artemisinin, orally administered at 10 and 50 mg kg−1 day−1, was compared in Plasmodium berghei infected mice. Subsequently, the pharmacokinetics of artelinic acid after intravenous, intramuscular, oral and rectal administration of a 20 mg kg−1 aqueous solution to rabbits were studied in a four-way randomized cross-over experiment. After intravenous administration, artelinic acid concentrations in blood plasma were high (C0: 76 ± 15 mg L−1), and the drug was rapidly eliminated from the central compartment, showing linear elimination kinetics with an elimination half-life of 15 ± 3 min. A large inter-subject variation appeared in the absorption rate and the extent of absorption (2–92%) over the 120 min interval after intramuscular administration. Also, a large inter-subject variation in individual rectal bioavailability (17–100%) was shown, which was dependent on the site of absorption in the rectum. The estimated oral bioavailability was low (4·6 ± 1·7%), probably due to a high first-pass effect and possible decomposition in the acidic gastric environment.
Stereoselective Interaction of Mianserin with 5-HT3 Receptors
Authors: Wood M D , Thomas D R , Watkins C J , Newberry N R
Published: April 2011

The interaction of the enantiomers of mianserin with the 5-HT3 receptor was determined. Using [3H]granisetron binding, (–)-mianserin was more potent than (+)-mianserin (pKi 8·46 and 6·95, respectively). The enantiomers competitively antagonized the depolarizing effect of 5-hydroxytryptamine in the rat vagus nerve preparation (pKapp: (–)-mianserin 8·13, (+)-mianserin 6·58). This stereoselectivity was maintained in-vivo as determined using ex-vivo inhibition of [3H]granisetron binding. Therefore, in contrast to its enantiomeric selectivity for the 5-HT1C and 5-HT2 receptors, where the (+)-isomer is more potent, the enantiomeric selectivity of mianserin for the 5-HT3 receptor was reversed. This differential selectivity of the enantiomers of mianserin may be useful in elucidating its utility in anxiety states.
Effect of macrolide antibiotics on ciliary motility in rabbit airway epithelium in-vitro
Authors: Takeyama Kiyoshi , Tamaoki Jun , Chiyotani Atsushi , Tagaya Etsuko , Konno Kimio
Published: April 2011

We have studied ciliary beat frequency (CBF) of rabbit cultured tracheal epithelium by a photoelectric method in-vitro. Addition of erythromycin and roxithromycin increased CBF in a dose-dependent fashion, whereas clarithromycin was without effect. The rank order potency of macrolide was roxithromycin > erythromycin » clarithromycin. The roxithromycin-induced increase in CBF was not altered by propranolol, AA-861, or verapamil, but partially attenuated by indomethacin. Roxithromycin increased intracellular cAMP concentrations. These results suggest that certain macrolides can stimulate airway ciliary motility probably via prostaglandin- and cAMP-dependent regulatory pathways, which may affect mucociliary transport function in the respiratory tract.
Extracellular 5-hydroxytryptamine concentration in rat hypothalamus after administration of fluoxetine plus l-5-hydroxytryptophan
Authors: Perry Kenneth W , Fuller Ray W
Published: April 2011

Fluoxetine (10 mg kg−1, i.p.) caused a three- to fourfold increase in extracellular 5-hydroxytryptamine (5-HT) concentration measured by microdialysis in hypothalamus of freely moving rats. The addition of l-5-hydroxytryptophan at 20 or 40 mg kg−1, i.p. doses, magnified the increase in extracellular 5-HT to as much as 16 times basal levels, although these doses of l-5-hydroxytryptophan alone had only small effects on extracellular 5-HT. The increased formation of 5-HT following l-5-hydroxytryptophan administration appears to overcome homeostatic mechanisms that limit the increases in extracellular 5-HT caused by uptake inhibition.
Platelet activating factor and the responses of rat isolated stomach strip to prostaglandin E2
Authors: Izzo A A , Mascolo N , Autore G , Capasso F
Published: April 2011

The effect of platelet activating factor (PAF) on contractions evoked by acetylcholine, 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) was studied in-vitro on rat stomach strip. Addition of PAF to the organ bath increased PGE- but not 5-HT- or acetylcholine-evoked responses. The effect of PAF was unaffected by atropine, methysergide or indomethacin, but prevented by a specific PAF receptor antagonist BN 52021. The data support a specific interaction between PAF and PGE2 on rat stomach strip.
Synthesis and Inverse Emulsion Polymerization of Aminated Acrylamidodextran
Authors: Daubresse C , Grandfils C , Jéräme R , Teyssié Ph , Goethals P , Schacht E
Published: April 2011

A chemically modified form of dextran was prepared, having a polymerizable moiety (acrylamide) and a reactive functional group (primary amine). Dextran was activated with 4-nitrophenyl-chloroformate (24 mol per polysaccharide, 9·8 mol per 100 glucose residues); 9·8% glucose residues were converted to aliphatic carbonates and 5·2% were converted to cyclic carbonates. The activated dextran was coupled with trityldiaminoethane (8 mol per 100 glucose residues), reactivated with 4-nitrophenylchloro-formate, then coupled with acryloamidodiaminohexane (6·8 mol per 100 glucose residues). The trityl group was removed by hydrolysis with trifluoroacetic acid to yield the required aminated acryloamidodextran. The modified dextran was shown to be polymerizable by inverse emulsion polymerization. Submicron particles were successfully prepared, containing functional amine groups suitable for preparing drug conjugates or for modifying the surface properties of this biomaterial.
Comparative Study on Inclusion Complexation of Maltosyl-β-cyclodextrin, Heptakis(2,6-di-O-methyl)-β-cyclodextrin and β-Cyclodextrin with Fucosterol in Aqueous and Solid State
Authors: Acartürk Füsun , Imai Teruko , Saito Hajime , Ishikawa Masahiro , Otagiri Masaki
Published: April 2011

The complexation of fucosterol with three kinds of β-cyclodextrin (β-CyD) was investigated in aqueous solution and in the solid state. The solubility of fucosterol increased significantly on its complexation with maltosyl-β-CyD and heptakis(2,6-di-O-methyl)-β-CyD (DM-β-CyD), while no appreciable increase was observed when complexed with β-CyD. The stability constant of complexation with β-CyD estimated from solubility determinations was greater for a 1:2 complex than for a 1:1 complex. On the other hand, 1:1 complexation of fucosterol with maltosyl-β-CyD or DM-β-CyD was greater than 1:2 complexation. The solid complexes were obtained in molar ratios of 1:2 and 1:3 for β-CyD and maltosyl-β-CyD complexes, respectively. The inclusion behaviour of fucosterol with maltosyl-β-CyD was compared with β-CyD in the solid state using DSC, powder X-ray diffractometry and CP/MAS 13C NMR. Maltosyl-β-CyD showed different inclusion behaviour compared with β-CyD, and produced an amorphous structure of fucosterol on complex formation. The dissolution rate of fucosterol-maltosyl-β-CyD complex was significantly faster than other complexes due to its high aqueous solubility and amorphous structure.
The Effect of the Cholecystokinin Antagonist Devazepide (L364718) on the Ileal Brake Mechanism in the Rat
Authors: Brown Nicola J , Rumsey R D E , Read N W
Published: April 2011

Studies were carried out on 28 male adult rats to investigate whether the selective cholecystokinin-receptor antagonist devazepide influences gastrointestinal transit under control conditions and when it is delayed by ileal infusion of lipid. Stomach-to-caecum transit time of the head of the test meal was measured using environmental hydrogen analysis and the distribution of the meal was assessed using the radiolabeled meal technique. Oral administration of devazepide (4 mg kg−1) had no significant effect on transit time of the head of the baked bean test meal under control conditions, but significantly reversed the delay in transit time induced by ileal infusion of lipid (P < 0·01). Studying the distribution of the meal showed that Intralipid delayed transit time by delaying both gastric emptying (P < 0·01) and small bowel transit (P < 0·05). Devazepide did not alter the control distribution of the meal during ileal saline infusion, but during ileal infusion of lipid, devazepide further delayed gastric emptying (P < 0·01); the geometric centre of the meal was situated more proximally in the gastrointestinal tract (P < 0·05), but there was more of the meal in the colon (P < 0·01). The latter is compatible with the early rise in environmental hydrogen during devazepide administration and ileal lipid infusion and suggests that peripheral cholecystokinin receptors may modulate or mediate the delay in small bowel transit induced by ileal lipid. However, the data also suggest that mechanisms other than those involving cholecystokinin play a dominant role in the regulation of postprandial and lipid-delayed gastric emptying of a meal.
Chemical Incompatibility Between Procainamide Hydrochloride and Glucose Following Intravenous Admixture
Authors: Sianipar A , Parkin J E , Sunderland V B
Published: April 2011

The chemical reaction between procainamide hydrochloride and glucose following admixture to glucose infusion has been investigated. Substantial amounts (10–15% after 10h at room temperature) of the procainamide is lost with the formation of a mixture of the corresponding α- and β-glucosylamines. The chemical identity of the latter compounds was confirmed by 13C and 1H nuclear magnetic resonance spectroscopy.
Distribution and Elimination of Sulphadimethoxine and Its Metabolites in Treated Chicken
Authors: Nagata Tomoko , Fukuda Yoshio
Published: April 2011

Sulphadimethoxine (SDM), and its metabolites, N4-acetyl SDM, N1-(2-methyl-6-hydroxy-4-pyrimidinyl) sulphanilamide (6-OH-SDM), N1-(6-methyl-2-hydroxy-4-pyrimidinyl) sulphanilamide (2-OH-SDM), N1-(2,6-dihydroxy-4-pyrimidinyl) sulphanilamide (2,6-diOH-SDM) and SDM N1-glucuronide in chicken tissues were extracted, partially purified by Bond Elute SCX cartridges, and assayed and identified by HPLC/LC-MS after administration of SDM to chickens. During the administration and 24 h after withdrawal, SDM and 6-OH-SDM were observed in almost all tissues and excreta. N4-Acetyl SDM and 2,6-diOH-SDM were observed in some tissues, but 2-OH-SDM and SDM N1-glucuronide were observed in a few limited tissues. Twenty four hours after withdrawal, SDM and its metabolites, except 6-OH-SDM, decreased. SDM and its metabolites were eliminated from all tissues within 48 h of withdrawal.
Curcuminoids as Potent Inhibitors of Lipid Peroxidation
Authors: Sreejayan  , Rao M N A
Published: April 2011

Earlier studies showed that curcumin is a potent inhibitor of iron-catalysed lipid peroxidation. Demethoxycurcumin, bisdemethoxycurcumin and acetylcurcumin were tested for their ability to inhibit iron-stimulated lipid peroxidation in rat brain homogenate and rat liver microsomes. Comparison of the results with curcumin showed that all compounds are equally active, and more potent than α-tocopherol. These results showed that the methoxy and phenolic groups contribute little to the activity. Spectral studies showed that all compounds could interact with iron. Thus, the inhibition of iron-catalysed lipid peroxidation by curcuminoids may involve chelation of iron.
Fenbufen Pretreatment Potentiates the Anticonvulsant Activity of CPPene and NBQX in DBA/2 Mice
Authors: De Sarro Giovambattista , Renne Stefania , Nava Felice , De Sarro Angela
Published: April 2011

The anticonvulsant activity of 3-((±)-2-carboxypiperazin-4-yl)-***l-propenyl-***l-phosphonic acid (CPPene) and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxoline (NBQX), two excitatory amino acid antagonists, was studied against audiogenic seizures in DBA/2 mice, following intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration. Maximal anticonvulsant protection was observed 15–30 min following NBQX and 45–180 min after CPPene. Coadministration with fenbufen (20mgkg-1, i.p.), a non-steroidal anti-inflammatory agent, enhanced and prolonged the anticonvulsant actions of CPPene and NBQX and also potentiated and prolonged the impairment of rotarod performance. The enhancement of the anticonvulsant activity and the prolonged impairment of rotarod performance suggests that fenbufen may have some pharmacokinetic interactions with CPPene and NBQX and that fenbufen is able to increase the brain levels of these excitatory amino acid antagonists. In particular, fenbufen was able to exert a major degree of potentiation of effects of NBQX rather than those of CPPene, suggesting that the chemical structures of these excitatory amino acid antagonists are responsible for the different degree of interactions between CPPene or NBQX and fenbufen. NBQX appears to have a notable similarity with quinolones whilst CPPene does not. Additionally fenbufen may displace CPPene and NBQX from plasma binding sites or inhibit the renal excretion. The present data are also consistent with previous studies showing pharmacokinetic interactions between fenbufen and quinolones.
Upregulation of antithrombotic ectonucleotidases by aspirin in human endothelial cells in-vitro
Authors: Cheung Po Kam , Visser Jan , Barker Winston W
Published: April 2011

Ecto ATP-diphosphohydrolase (apyrase) activity of human endothelial cells following aspirin treatment has been studied in-vitro. It was shown by HPLC analysis of supernatant samples that pre-incubation of the cultures with aspirin resulted in a significantly increased turnover of supplemented ATP into its degradation products (ADP and AMP). Enhanced expression of ectoenzyme after aspirin treatment could be observed as demonstrated by immunofluorescence-staining with monoclonal anti-apyrase antibodies. This suggests enhancement of endothelial ATP-diphosphohydrolase activity induced by aspirin. The present data obtained in human vascular cells in-vitro are in line with results from previous animal studies in-vivo, suggesting a novel cyclo-oxygenase-independent antithrombotic activity of aspirin.
Incorporation of α-Tocopherol in Liposomes Promotes the Retention of Liposome-encapsulated Glutathione in the Rat Lung
Authors: Suntres Z E , Shek P N
Published: April 2011

The present study was undertaken to investigate whether α-tocopherol incorporated in liposomes could improve the retention of entrapped glutathione (GSH) in the lung following intratracheal instillation in rats. Rats were treated with a single dose of [3H]GSH entrapped in liposomes with or without 30 mol% α-tocopherol and killed 0, 24 or 48 h later. The retention of GSH in the lung was assessed by measuring the recovery of either 3H-label or GSH in the lung. Animals instilled with free [3H]GSH were found to retain only 2% of the administered dose at 24 h after treatment and no detectable radioactivity at 48 h. Liposome encapsulation altered the pulmonary retention of GSH with 18 and 10% of radioactivity remaining in the lung at 24 and 48 h post-treatment, respectively. The instillation of GSH encapsulated in α-tocopherol-containing liposomes resulted in the highest level of GSH retention in the lung, namely 37 and 30% of the administered GSH dose at 24 and 48 h, respectively. Results from Sepharose 4B column chromatography revealed that lung homogenates, obtained from rats instilled with GSH entrapped in α-tocopherol-containing liposomes, 24 and 48 h earlier, contained 2 eluted GSH-related components—one associated with the liposomal lipid marker in the void volume and the other as free GSH tripeptide, suggesting a slow sustained release effect mediated by the liposomal formulation. The same liposome preparation containing both α-tocopherol and GSH also conferred better protection against FeADP-induced lipid peroxidation than liposomes containing either α-tocopherol or GSH alone, indicative of a potentially effective antioxidant formulation for treating oxidative lung injury.
Ex-vivo and In-vivo Antithrombotic Effect of Triflavin, an RGD-containing Peptide
Authors: Sheu J R , Huang T F
Published: April 2011

Triflavin, an Arg-Gly-Asp-containing snake venom peptide, inhibits platelet aggregation through the blockade of fibrinogen binding to the activated platelets. It binds to fibrinogen receptors associated with the glycoprotein IIb/IIIa complex with a Kd value of 7 × 10−8 m. In this study, we found that 125I-triflavin reached the maximal binding to human platelets within 5 min at 25°C. In addition, when triflavin was intravenously administered at 1·0 mg kg−1 to rabbits, it reversibly impaired the platelet aggregation of platelet-rich plasma caused by ADP (20 μm) ex-vivo over 30 min. The platelet counts of the experimental rabbits remained unchanged. Triflavin was effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism in mice when administered intravenously at a dose of 2 μg g−1. Therefore, triflavin was proven to be an effective antithrombotic agent in preventing ADP-induced acute pulmonary thromboembolism in mice and impairing reversibly the platelet function of rabbits when given intravenously.
The effect of colestipol and cholestyramine on the systemic clearance of intravenous ibuprofen in rabbits
Authors: El-Sayed Yousry M , Al-Meshal Mohamed A , Al-Angary Abdulaziz A , Lutfi Khalil M , Gouda M Wafik
Published: April 2011

The effect of oral administration of the non-absorbable anion-exchange resins cholestyramine and colestipol on the systemic clearance and other pharmacokinetic parameters of intravenously administered ibuprofen (25 mg kg−1) was studied in rabbits. Single doses of colestipol hydrochloride (0·4 g kg−1) or cholestyramine (0·17 g kg−1) were given 30 min before ibuprofen administration. In cholestyramine-treated rabbits a significant reduction in ibuprofen plasma concentration was observed compared with both control (water only) and colestipol-treated rabbits. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half-life and the mean residence time. Furthermore, a 31% increase in the systemic clearance and 23% decrease in the area under the plasma concentration-time curve were also observed in cholestyramine-treated rabbits. Colestipol treatment did not change these parameters. The volume of distribution parameters (Vdss and Vdarea) did not change following either treatment. The changes in the pharmacokinetic parameters are compatible with an acceleration of ibuprofen elimination induced by oral administration of cholestyramine and not by colestipol. This effect is thought to be due to augmentation of net biliary excretion through enteric binding.
Location of Probucol in Lipoproteins Inferred from Compositional Analysis of Lipoprotein Particles. An In-vitro Study
Authors: Bard Jean-Marie , Urien Saîk , Fruchart Jean-Charles , Tillement Jean-Paul
Published: April 2011

The location of labelled probucol in lipoprotein particles was investigated in-vitro. Human serum was incubated for 4 h at 37°C with [14C]probucol to incorporate probucol into lipoproteins. Serum lipoprotein particles were then isolated according to their apolipoprotein markers by sequential immunoaffinity chromatography at 4°C, and probucol concentration was determined in each lipoprotein fraction. Analysis of probucol distribution vs lipoprotein components revealed that probucol in particles strongly correlated with phospholipid concentration. Analysis of probucol distribution vs lipoprotein physical characteristics showed that probucol strongly correlated with the surface area of the monolayer surrounding the lipidic core of particles constituting phospholipids and free cholesterol. These data support the hypothesis that probucol is preferentially located in the phospholipid/free cholesterol monolayer surrounding the lipid core, in the vicinity of cholesteryl ester at the core surface or in the vicinity of hydrophobic areas of apolipoprotein that faces the monolayer.