bluuebunny/crossref_metadata_2025 huggingface dataset:
The guinea-pig trachea O-methylating system is more effective in modulating β2- than β1-adrenoceptor-mediated responses to isoprenaline
Authors: Proença J , Paiva M Q , Guimarāes S
Published: April 2011

Assuming that responses of the guinea-pig trachea to isoprenaline in the presence of atenolol (10 μmol L−1) are exclusively, or at least predominantly, (β2-adrenoceptor mediated and that responses to isoprenaline in the presence of ICI 118,551 (erythro-DL-1(7-methylindan-4-yloxyl)-3-isopropylaminobutan-2-ol) (1 nmol L−1) are exclusively, or at least predominantly (β1-adrenoceptor mediated, the influence of inhibition of COMT by U-0521 (dehydroxy-2-methyl propiophenone) (50 μmol L−1) has been compared in both conditions. U-0521 enhanced (β2-adrenoceptor mediated responses to isoprenaline 3-3-fold, while those mediated by (β1-adrenoceptors were enhanced only 2-2-fold. It is concluded that in guinea-pig trachea COMT activity is functionally more effective in modulating responses which are mediated by β2-adrenoceptors than responses mediated by β1-adrenoceptors.
The structure of phenindamine base and salts in the solute state
Authors: Branch S K , Casy A F , Hussain R , Upton C
Published: April 2011

High-field NMR (13C and 1H) studies of phenindamine are reported which establish structures of the free base and some of its salts in the solute condition. The base exists as a mixture of two isomers which differ in double bond position (9–9a or 4a–9a) while most salts are 9–9a isomers. The clinically employed tartrate (Thephorin) is exceptional in being a 4a–9a ene. Salts of both double bond type exist in solution as mixtures of protonated epimers of variable epimeric ratio, that of the tartrate in D2O being approximately 1:1.
Variation of Population Release Kinetics in Polydisperse Multiparticulate Systems (Microcapsules, Microspheres, Droplets, Cells) with Heterogeneity of One, Two or Three Parameters in the Population of Individuals
Authors: Donbrow Max , Hoffman Amnon , Benita Simon
Published: April 2011

Release kinetics of active substances from ensembles of microparticles such as microcapsules, cells, droplets and liposomes constituted of individual entities releasing their contents at constant rates may follow zero order, first order, sigmoid or biphasic equations. The release equation observed depends upon the statistical distribution of release-determining parameters among the population. Typical cases are presented in terms of the distribution of two parameters, payload (m∞ and time for complete payload release (t∞) which also define the release rate constant (k). Heterogeneity of the two parameters generally leads to first order ensemble behaviour, whereas heterogeneity of one parameter only may lead to different ensemble release equations, viz. zero order (m∞ heterogeneous) or first order (t∞ heterogeneous). Biphasic distribution can lead to an apparent ‘burst’ effect, with apparent change of kinetics. The presence of a third heterogeneous parameter, lag time, yields a sigmoid ensemble release curve. These conclusions are demonstrated by simulations or experimentally, and are also valid for linearized curves of microparticles following matrix kinetics.
The influence of binder film thickness on the mechanical properties of binder films in tension
Authors: Ononokpono Okon E , Spring M S
Published: April 2011

The physicomechanical properties of films of different thicknesses, made from methylcellulose and gelatinized maize starch, have been studied in tension. There was a linear relation between film thickness and tensile strength, toughness, elastic resilence and elongation at fracture. Young’s modulus increased with decreasing film thickness particularly with films with a thickness of less than 15 μM.
Lipid solubility of a series of drugs and its relevance to fatal poisoning
Authors: Cassidy S L , Lympany P A , Henry J A
Published: April 2011

For 11 commonly used drugs, the n-octanol/water partition coefficient (pH 7.4 temperature 37°C) and solubility in n-octanol were determined. The drugs tested were chlorpromazine, amitriptyline, trazodone, dextropropoxyphene, diltiazem, dibucaine, amethocaine, procaine, quinidine, acetylsalicylic acid and paracetamol. For eight of the drugs, the relative lipid saturation corresponding to a fatal plasma concentration was estimated from the two parameters determined above and the median fatal blood concentrations reported in the literature. For five of those eight drugs, the estimated relative saturation in the lipid phase fell within the range 0.001–0.004 which is close to relative saturation figures in aqueous and vapour phases already published for chemicals possessing a non-specific or physical mechanism of toxicity. Since this is determined largely by their lipid solubility, it is probable that accumulation in the lipid phase is an important determinant of the lethal toxicity of drugs and chemicals with a non-specific mechanism of toxicity.
Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.
Authors: Formukong Evelyn A , Evans A Tudor , Evans Fred J
Published: April 2011

Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.
Inhibition of thromboxane biosynthesis by 3-pyridinol carboxypentyl ethers substituted with a hydroxylated octyl chain
Authors: Conti S , Desideri N , Passaghe S , Castagnoli M N , Cerletti C , Stein M L
Published: April 2011

Racemic 6-[4-(3′-hydroxy-l′-octenyl)-3-pyridyloxy] hexanoic and 6-[4-(3′-hydroxyoctyl)-3-pyridyloxy] exanoic acids have been synthesized and their activity as inhibitors of the biosynthesis of thromboxane A2 in human serum has been studied, in comparison with isomers having the eight-carbon chain in the 2 position. Very high, selective activity was found for the new 4-substituted 3-pyridinol ethers, whereas the 2-substituted compounds showed no action.
Effect of sodium valproate on midazolam distribution
Authors: Calvo R , Suárez E , Rodríguez-Sasiaín J M , Aguilera L
Published: April 2011

The displacement of midazolam, a new water-soluble, short-acting benzodiazepine, from its plasma binding sites by sodium valproate, has been studied in man. An increase of its free fraction (ranging from 2.71 to 5.35%) in plasma from epileptic patients receiving sodium valproate was observed. A similar situation was created in rabbits by pretreatment with sodium valproate (600 mg kg−1 day−1) and posterior hypnosis with midazolam. Due to the interaction, sodium valproate-pretreated rabbits showed an increase in midazolam brain levels (130.91 μg g−1 in cortex vs 84.55 μg g−1 in control animals). Therefore, it seems likely that displacement of midazolam by sodium valproate in epileptic patients could lead to an increase of the midazolam response.
Repeated treatment with imipramine and amitriptyline reduced the immobility of rats in the swimming test by enhancing dopamine mechanisms in the nucleus accumbens
Authors: Cervo Luigi , Samanin Rosario
Published: April 2011

Bilateral injections of 1 μg sulpiride in the rat nucleus accumbens antagonized the effect of a seven-day treatment with 20 mg kg−1 day−1 imipramine or amitriptyline in the swimming test. The data suggest that dopamine mechanisms in the limbic regions of the rat brain are involved in the effect of repeated treatment with imipramine and amitriptyline in that test.
Vesicular Systems (Niosomes and Liposomes) for Delivery of Sodium Stibogluconate in Experimental Murine Visceral Leishmaniasis
Authors: Hunter C A , Dolan T F , Coombs G H , Baillie A J
Published: April 2011

Suppression of Leishmania donovani liver amastigotes by sodium stibogluconate has been determined in a murine model of experimental visceral leishmaniasis. Niosomal and liposomal drug formulations were equiactive and both increased drug efficacy by an order of magnitude compared with that of free drug. Niosomes containing 30 mol % cholesterol were prepared from three different non-ionic surfactants and no significant difference in activity was detected among the different drug-loaded niosomes. Both negatively charged and neutral vesicles were found to be equally effective. However, vesicle cholesterol content had a slight influence on the antiparasitic activity of the drug-loaded niosomes. Empty vesicles produced a dose-dependent parasite suppression for all vesicles studied. Studies of antimony distribution in the mouse using neutron activation analysis showed high liver levels after i.v. administration of the carrier forms of the drug.
Association of Liposome-entrapped [3H]Methotrexate with Thioglycollate-elicited Macrophages In-vitro
Authors: Foong W C , Green K L
Published: April 2011

The association of free or liposome-entrapped [3H]methotrexate ([3H]MTX) with thioglycollate-elicited macrophages was investigated in-vitro. [14C]Cholesteryl oleate was incorporated into the liposomes as a lipid marker. [3H]MTX association with the macrophages was 5 to 9-fold higher with liposome-entrapped [3H]MTX than with the free drug. Macrophage-liposome association was biphasic, temperature-dependent and saturable at high liposomal lipid concentration. A high liposome cholesterol (CH) content or the presence of 2,4-dinitrophenol or colchicine also reduced macrophage-liposome association.
Evaluation of Different Drugs in Two Models of Immediate Hypersensitivity
Authors: Ayala L E , Aleixandre M A , Mora L García
Published: April 2011

The effect of the calcium antagonists, verapamil, nicardipine and diltiazem, the two cromones, disodium cromoglycate and SM-857 (11-oxo-11 H-pyrido[2,1-b]quinazoline-2-carboxylic acid), and the anthelmintic, diethylcarbamazine citrate, have been compared on the ovalbumin (OA)-induced contraction of the isolated trachea and longitudinal muscle-myenteric plexus (LM-MP) from sensitized guinea-pigs. The calcium antagonists prevented the OA-induced contractions in LM-MP and to a lesser degree the OA-induced contractions in trachea. Similar doses of SM-857 protected both tissues but neither cromoglycate (10−5M) nor diethylcarbamazine (10−5M) affected these contractions. The OA-induced contraction in trachea had a tonic phase that was not present in the LM-MP response. Only the calcium antagonists succeeded in relaxing this OA tonic component, diltiazem being the more potent. These results unmask different mechanisms of drug action on immediate hypersensitivity and specific sensibilities, depending on the kind of tissue.
Contractile activity of calcitonin gene-related peptide on pulmonary tissues
Authors: Hamel R , Ford-Hutchinson A W
Published: April 2011

Rat calcitonin gene-related peptide was shown to be a very potent contractile agent on guinea-pig trachea, contractions being observed at 10 pM and maximal contractions (32–36% of the methacholine maximum) being observed between 0.3 and 13.3 nM. The response was largely inhibited (88%) by pretreatment with indomethacin indicating that the effect was mediated through the secondary generation of cyclooxygenase products.
Kinetic mechanism for the intestinal absorption of ofloxacin
Authors: Prieto J G , Barrio J P , Alvarez A I , Gómez G
Published: April 2011

The absorptive behaviour of ofloxacin, a quinolone antibacterial agent, was studied following recirculation in small intestine of both male and female rats, at initial doses ranging from 0.125 to 5 mg mL−1. A saturable Michaelis-Menten process is suggested to explain the intestinal absorption. No significant differences were found in the absorption parameters per metabolic weight unit.
β-Adrenoceptor stimulating effects of phenylephrine and noradrenaline in the rat pulmonary vascular bed
Authors: Uma S , Tuncer M
Published: April 2011

The effects of phenylephrine and noradrenaline have been investigated on the perfusion pressure of the rat isolated lung. Both drugs (0.3–30 μg) produced a dose-dependent decrease in perfusion pressure elevated by 20 mM KCl, which was reversed to a dose-dependent increase after addition of propranolol (1 × 10−7 M) to the perfusion fluid. Increments due to both agonists in the presence of propranolol were antagonized by prazosin (1 × 10−6 M). Propranolol, but not prazosin, elevated the basal perfusion pressure. The results indicate that phenylephrine and noradrenaline are more effective in stimulating β-adrenoceptors than α-adrenoceptors in the rat pulmonary vascular bed and that β-adrenoceptors may regulate the vascular tone of the rat pulmonary circulation.
High doses of L-naloxone but neither D-naloxone nor β-funaltrexamine prevent hyperthermia-induced seizures in rat pups
Authors: Laorden M L , Miralles F S , Puig M M
Published: April 2011

The effects of the non-specific opiate antagonist L-naloxone and the inactive isomer D-naloxone, as well as the specific mu receptor antagonist β-funaltrexamine, have been examined on hyperthermia-induced seizures in unrestrained 15 days old rats. Saline-injected animals exposed to an ambient temperature of 40°C showed a gradual increase in body temperature reaching a maximum of 42±0.1°C at 50 min exposure. At this time all the pups had seizures and died. Similar results were obtained when the animals were pretreated with different doses of D-naloxone and β-funaltrexamine. Rats pretreated with L-naloxone also showed an increase in rectal temperature; but the temperature was lower than in saline-injected animals. Only high doses of L-naloxone prevented seizures and deaths. These data indicate that endogenous opioid peptides may play a role in seizures induced by hyperthermia and that receptors other than mu receptors could be involved in hyperthermia-induced seizures.
Proteoglycan biosynthesis as a determinant of patella damage in the murine antigen-induced arthritis model
Authors: Steward A , Rising T J , Bottomley K M K , Haddrell L
Published: April 2011

The incorporation of 35SO4 into cartilage proteoglycan has been employed as a measure of patella damage in the murine antigen-induced arthritis model. In a preliminary set of experiments, where both the proteoglycan concentration and 35SO4 incorporation were determined in control and arthritic patella over a 2 day to 6 day week period, the arthritic joint contained significantly higher levels of radioactivity compared with the controls. A subsequent study over an extended period of 10 weeks confirmed the earlier results, and indicated that the 6 week samples showed the greatest difference (71%) in 35SO4 incorporation between the arthritic and control patella.
Non-ionic Surfactant Effects on Hairless Mouse Skin Permeability Characteristics
Authors: Walters Kenneth A , Walker Michael , Olejnik Orest
Published: April 2011

The influence of a range of polyethoxylated non-ionic surfactants upon the transport of methyl nicotinate across hairless mouse skin in-vitro was investigated using standard two-compartment diffusion cells. Those surfactants having a linear alkyl chain greater than C8 and an ethylene oxide chain length of less than E14 caused significant increases in the flux of methyl nicotinate. Surfactants having branched or aromatic moieties in the hydrophobic portion were ineffective. Maximum enhancement of flux was obtained using polyoxyethylene (10) lauryl ether (Brij 36T). Two possible modes of surfactant action are proposed. Initially the surfactant may penetrate into the intercellular regions of the stratum corneum, increase fluidity and eventually solubilise and extract lipid components. Secondly, penetration of the surfactant into the intracellular matrix followed by interaction and binding with the keratin filaments may result in a disruption of order within the corneocyte. The structural specificity required for the latter mechanism may explain, to some extent, the maximum activity obtained with the C12 surfactant.
Effects of Methylene Blue on the Uptake, Release and Metabolism of Noradrenaline in Mesenteric Arterial Vessels
Authors: Soares-da-Silva P , Caramona M M
Published: April 2011

Methylene blue (3, 10 and 30 μM) increased the spontaneous outflow of endogenous dopamine and noradrenaline from sympathetic nerves supplying the dog mesenteric artery and drastically reduced the formation of endogenous dihydroxyphenylglycol (DOPEG). In addition, it decreased the accumulation of [3H]noradrenaline in the tissue, reduced the formation of [3H]DOPEG and [3H]normetanephrine, without altering the formation of [3H]dihydroxymandelic acid. In tissue homogenates of the same blood vessel, methylene blue 30 and 100 μM produced a significant reduction in the deamination of 5-hydroxytryptamine (5-HT), β-phenylethylamine (β-PEA) and tyramine. Methylene blue increased the accumulation of [3H]isoprenaline in the tissue, and markedly reduced the formation of [3H]O-methylisoprenaline ([3H]OMI). These results show that methylene blue alters the storage and disposition of the adrenergic transmitter.
Pharmacological Modulation of Platelet Activating Factor (PAF)-induced Bronchoconstriction and Hypertension in Anaesthetized Guinea-pigs
Authors: Iwama Takehisa , Shikada Ken-Ichi , Tanaka Sakuya
Published: April 2011

The effect of PAF has been examined in anaesthetized guinea-pigs. Intravenous (i.v.) administration of PAF (10 ng kg−1) did not modify the respiratory response but decreased the arterial blood pressure. A high dose of PAF (200 ng kg−1) caused marked bronchoconstriction and concomitant hypertension. The cyclooxygenase inhibitors aspirin (5 mg kg−1) and indomethacin (5 mg kg−1) and the thromboxane A2 (TXA2) receptor antagonist BM-13.177 (1 mg kg−1) failed to inhibit the peak bronchoconstrictive response but significantly inhibited the prolonged response following peak response. These inhibitors also attenuated PAF-induced hypertension. On the other hand, the lipoxygenase inhibitors phenidone (10 mg kg−1) and NDGA (5 mg kg−1) and the leukotriene (LT) receptor antagonist FPL-55712 (2 mg kg−1) affected neither bronchoconstriction nor hypertension induced by PAF. However, when aspirin was given in combination with NDGA, phenidone or FPL-55712, the peak and the following prolonged bronchoconstriction were significantly inhibited. The suppression of PAF-induced hypertension by aspirin was not further inhibited by the combination of these inhibitors. These results indicate that in anaesthetized guinea-pigs PAF-induced bronchoconstriction is composed of a dual response, a direct action (peak response) and an indirect action (prolonged response). The latter may be produced by the generation of TXA2 and lipoxygenase products, while PAF-induced hypertension is indirectly mediated by the generation of TXA2.
[3H]Zacopride: Ligand for the Identification of 5-HT3 Recognition Sites
Authors: Barnes N M , Costall B , Naylor R J
Published: April 2011

[3H]Zacopride displayed saturable binding to homogenates of the rat entorhinal cortex as measured by the inclusion of the 5-HT3 receptor antagonist BRL 43694 in the incubation media. Scatchard analysis indicated a single high affinity binding site (KD 0.76 ± 0.08 nM, Bmax 77.5 ±6.5 fmol (mg protein)−1) with a Hill slope close to unity. Other 5-HT3 receptor antagonists (zacopride, ICS 205–930, GR38032F, GR65630, metoclopramide and cocaine) also competed for the binding site displacing 60% of the total [3H]zacopride binding. 5-HT and 2-methyl-5-HT also were competitive antagonists for [3H]zacopride binding whereas 5-HT1/5-HT2 agonists and antagonists, and agents acting on other neurotransmitter receptors had Ki values greater than 10−5 M. It is concluded that [3H]zacopride may prove a useful ligand for the study of 5-HT3 recognition sites.
Variations in the friction coefficients of tablet lubricants and relationship to their physicochemical properties
Authors: Baichwal A R , Augsburger L L
Published: April 2011

A previously described modified annular shear cell (MASC) has been used to measure the friction coefficients of some powdered tablet lubricants on a steel surface. Commonly used lubricants, as well as others belonging to the stearate group, differed in their friction coefficients at equivalent sample sizes and in the degree of their ability to reduce friction with increasing amounts when evaluated by the apparatus. In all comparisons, magnesium stearate had the lowest friction coefficient. Divalent salts of stearic acid appeared to be better than the other lubricants tested, and among themselves differed only in the extent of their ability to decrease friction. The lubricants also differed in their physical and chemical properties. On evaluation by stepwise regression analysis, such physical properties as projected surface area of lubricant particles, Martin’s diameter and bulk density accounted for most of the variation in friction coefficients of the lubricants rather than moisture content or melting point. It could therefore be suggested that particle size and/or surface area parameters be incorporated in product specifications to ensure reproducible functionality.
Dopamine receptor modulation of corticosterone secretion in neonatal and adult rats
Authors: Kitchen Ian , Kelly Mary , Turner Michelle
Published: April 2011

The effects of the dopamine agonist, pergolide, upon plasma corticosterone levels have been studied in 30 day old neonatal and adult rats. Dose-related elevations in corticosterone were observed at both ages and these elevations were blocked by the dopamine (D2) receptor antagonist spiperone. These studies demonstrate that dopaminergic neurochemical control of the hypothalamus-pituitary-adrenal axis exists in four week old rats in contrast to our previous studies which have shown opioid control to be absent at this age. It appears that neurochemical control of corticosterone is dissimilar in the neonate.
Influence of Lipophilicity and Chirality on the Selectivity of Ligands for β1- and β2-Adrenoceptors
Authors: Tayar Nabil El , Testa Bernard , van, de Waterbeemd Han , Carrupt Pierre-Alain , Kaumann Alberto J
Published: April 2011

Eudismic and QSAR analyses are reported for the β1- and β2-adrenoceptor affinities and β1-selectivity of 10 enantiomeric pairs of ligands with only N-isopropyl or N-t-butyl groups. For both receptors, the eudismic index (ratio of affinity) increases with the affinity of the eutomers. However, the affinity of the distomers for the β2-adrenoceptor is relatively high, suggesting additional hydrophobic interactions. This is confirmed by various correlations between affinities and lipophilicities, showing that the affinity for β2-adrenoceptors is slightly more dependent on lipophilicity than that for β1-adrenoceptors. As a result, the β1-selectivity of the investigated β1-adrenoceptor ligands is strongly and negatively correlated with their lipophilicity (r = −0.942).
Definition of the In-vivo Accumulation of [3H]spiperone in Brain using Haloperidol and Sulpiride to Determine Functional Dopamine Receptor Occupation
Authors: Chivers J K , Reavill C , Jenner P , Marsden C D
Published: April 2011

The in-vivo administration of [3H]spiperone caused an accumulation of radioactivity in the substantia nigra, tuberculum olfactorium, nucleus accumbens, striatum and frontal cortex when compared with cerebellar levels. Haloperidol (0.01–1.0 mg kg−1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone in the substantia nigra, tuberculum olfactorium, striatum and nucleus accumbens. Sulpiride (10–160 mg kg−1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone only in the substantia nigra. The effects of sulpiride on other areas were not consistent; there was a suggestion of a reduction in the accumulation of [3H]spiperone in tuberculum olfactorium and striatum, but not in nucleus accumbens. Neither haloperidol (0.01–1.0 mg kg−1 i.p.) nor sulpiride (10–160 mg kg−1 i.p.) caused displacement of [3H]spiperone from the frontal cortex. Both haloperidol (0.01–0.5 mg kg−1) and sulpiride (10–80 mg kg−1) increased striatal and mesolimbic HVA concentrations. Haloperidol potently blocked apomorphine-induced stereotypy but sulpiride was only effective at the highest dose employed. The functional effect produced by haloperidol correlated with its ability to define [3H]spiperone binding in-vivo to dopamine receptors in the substantia nigra, striatum and tuberculum olfactorium. In contrast, there was no correlation between functional effect of sulpiride and its ability to define [3H]spiperone binding in-vivo.
Intestinal absorption of cephalosporin antibiotics: correlation between intestinal absorption and brush-border membrane transport
Authors: Hori Ryohei , Okano Tomonobu , Kato Miyako , Maegawa Hitoshi , Inui Ken-Ichi
Published: April 2011

The absorption of seven cephalosporin antibiotics from the in-situ intestinal loop at pH 7.4 and their transport by brush-border membrane vesicles in the presence of an inward H+ gradient ([pH]i = 7.5, [pH]o = 6.0) were examined. A good correlation was found between the intestinal absorption rate and the initial uptake rate by brush-border membrane vesicles. The data suggest that the transport study using intestinal brush-border membrane vesicles is useful as a model system for the intestinal absorption of β-lactam antibiotics.
Effects of proenkephalin products on rat cardiac and vascular tissue in-vitro
Authors: Douglas H , Kitchen I
Published: April 2011

The cardiovascular effects of the four proenkephalin products [Metl-enkephalin (ME), [Leu]-enkephalin (LE), [Met]-enkephalyl-arg6phe7 (MEAP) and [Met]-enkephalyl-arg6-gly7-leu8 (MEAGL) have been studied on the isolated spontaneously beating rat atria and the perfused rat mesentery in-vitro. All four peptides (at concentrations up to 10−6M and in the presence of peptidase inhibitors) had no direct effect on atrial rate or contractility and did not alter responses to noradrenaline or field stimulation. In addition, the peptides had no effect on the perfusion pressure of the mesentery and did not alter vasoconstrictor responses to noradrenaline. The results show that proenkephalin products are without direct or modulating effects on atrial muscle or mesenteric vasculature of the rat, and suggest that there is no endogenous opioid control in these tissues.
Excretion and distribution of [14C]rhein and [14C]rhein anthrone in rat
Authors: de Witte P , Lemli J
Published: April 2011

After single intracaecal administration of [14C]rhein (25 mg kg−1) and [14C]rhein anthrone (20 mg kg−1) to rats, the summated recovery rates of 14C after five days were in urine 37(±8.3)% and 2.8(±0.4)% and in faeces 53(±9.5)% and 95 (±10.1)%, respectively. The clearance of radioactivity from the organs and tissues was almost complete within three days, with the exception of the kidney which exhibited pronounced retention of radioactivity even after five days (<61% of 24 h values). Extracts of faeces from animals treated with [14C]rhein of [14C]rhein anthrone, revealed rhein as well as other radioactive substances, which chemically did not react as 1,8-dihydroxyanthraquinones.
The influence of concentration of two salicylate derivatives on rectal insulin absorption enhancement
Authors: Hauss David J , Ando Howard Y
Published: April 2011

3,5-Diiodosalicylate sodium (DIS), a highly lipophilic salicylate, was evaluated against 5-methoxysalicylate sodium (MS) as a potential adjuvant absorption promoter for rectal insulin delivery. Comparative blood glucose measurements were made using the two adjuvants under identical conditions as promoters of rectal insulin absorption in rats. Concentrations of DIS greater than and including 0.1 M produced an unexpected, progressive decrease in adjuvant activity as determined by a decline in observed hypoglycaemic response. This was not due to formation of an insulin-DIS complex. The adjuvant MS produced a classical, sigmoidal log-dose response curve. Possible reasons for the occurrence of the DIS optimum phenomenon are discussed as well as are the observed differences in adjuvant potency of these agents in a propylene glycol-containing vehicle.
New method for testing the absorbency of surgical dressings
Authors: Betts T J , Czarniak Petra A , Filippin Patricia
Published: April 2011

Absorbent cellulose dressings have been tested by immersion in a standard aqueous solution of picric acid followed by standard draining, elution of the picric acid, and measurement of the absorbance of the yellow colour at 355 nm. Six samples of gauze were graded by this procedure, and two considered unsatisfactory, despite all sinking in less than 10s. Filmated gauzes and unwoven dressings required greater dilution for the absorbance readings, reflecting their different structures.
A Consideration of the Range and Strength of Interparticle Forces in Coated Lactose Powder
Authors: Igwilo C , Pilpel N
Published: April 2011

A study has been made of the range and strength of interparticle forces in lactose powder coated with increasing concentrations of paraffins at different temperatures. Marked changes occurred in these forces as the paraffin content was altered and the temperature increased from − 10° to + 50°C. The strength and range of interparticle forces depended on the mechanical properties of the coating materials and the surface free energy of the coated powders.
Activities of Octopamine and Synephrine Stereoisomers on Octopaminergic Receptor Subtypes in Locust Skeletal Muscle
Authors: Evans Peter D , Thonoor C Mohan , Midgley John M
Published: April 2011

The activities of the (−) and (+)- forms of p-, m- and o- octopamine and p- and m- synephrine have been compared on the different subtypes of octopamine receptor present in the extensor-tibiae neuromuscular preparation from the locust hindleg. The rank order of potency of the (−)-forms on the OCTOPAMINE2A receptors was p-synephrine > p-octopamine > m-octopamine > o-octopamine > m-synephrine whilst the rank order of the (+)-forms was p-synephrine > p-octopamine > m-octopamine. (+)-m-Synephrine and (+)-o-octopamine had no effect on this class of receptor when tested up to a concentration of 10−3M. The rank order of potency of the (−)-forms on the OCTOPAMINE2B receptors was p-synephrine > p-octopamine > m-synephrine > m-octopamine > o-octopamine whilst the rank order of the (+)-forms was p-octopamine > p-synephrine > m-octopamine > o-octopamine. (+)-m-Synephrine again had no effect up to a concentration of 10−3M. The rank order of potency of the (−)-forms ontheOCTOPAMINE1 receptors was p-synephrine > p-octopamine > m-synephrine > m-octopamine > o-octopamine, whilst the rank order of the (+)-forms was p-synephrine > p-octopamine > o-octopamine > m-synephrine > m-octopamine. In all cases the (−) enantiomers of all the structural isomers tested were more potent than the corresponding (+)-forms with isomeric activity ratios varying between 2 and 480. The activities of the octopamine and synephrine stereoisomers on the different octopamine receptor subtypes in the locust are compared with their published activities on the subtypes of mammalian α- and β-adrenoceptors.
Postnatal behavioural effects of maternal nicotine exposure in rats
Authors: Fung Y K
Published: April 2011

The effects of nicotine on locomotor activity have been studied in neonate rats exposed to nicotine (1.5 mg kg−1 day−1) throughout the gestational period. Both 14 day old male and female offspring demonstrated an increase in spontaneous locomotor activity when compared with saline-exposed controls. However, systemic administration of (+)-amphetamine was effective in attenuating the hyperactivity of these nicotine-exposed pups.
Stimulation of Gastric and Colonic Mucosal Eicosanoid Synthesis by Plantain Banana
Authors: Goel R K , Tavares I A , Bennett A
Published: April 2011

Extracts of plantain banana (Musa sapientum Linn var. paradisiaca) were studied on the accumulation of eicosanoids in incubates of human gastric and colonic mucosa. The ethanolic extract caused a concentration-dependent increase in the eicosanoid accumulation but the water extract was ineffective. Since all the eicosanoids studied tended to increase, banana may act by increasing the availability of arachidonate. In control tissues the accumulation of PGE and TXB2 in the incubates decreased with time while that of 6-keto-PGF1α increased (colon only, studied).
Biocompatibility of Wound Management Products: Standardization of and Determination of Cell Growth Rate in L929 Fibroblast Cultures
Authors: Turner Terence D , Spyratou Olga , Schmidt Richard J
Published: April 2011

To facilitate the development of a bioassay procedure by which the biocompatibilities of materials used in wound management may be assessed and compared, those environmental factors affecting cell growth in mouse L929 fibroblast cultures have been identified. Standardization of the initial cell number and frequency of change of medium resulted in the virtual elimination of variation of growth curves of L929 cells cultured in flasks of specified surface area. In addition, three methods for assessing fibroblast growth rate in the presence of alginate products used in wound management were evaluated. These were the haemacytometer counting chamber method, the Coulter counting method, and a liquid scintillation counting method. The first two methods determine the number of cells in a given volume of a cell suspension, whereas the third method determines the rate of synthesis of deoxyribonucleic acid (DNA), and hence cell growth, by measuring the incorporation of [3H]thymidine. The haemacytometer method had significant advantages over the other two procedures in providing both qualitative and quantitative data on culture morphology and cell growth response.
Transport of cephalosporin antibiotics in rat renal basolateral membranes
Authors: Takano Mikihisa , Okano Tomonobu , Inui Ken-Ichi , Hori Ryohei
Published: April 2011

Transport mechanisms of cephalosporin antibiotics in rat renal basolateral membranes have been studied in isolated membrane vesicles. Uptake of [14C]p-aminohippurate, a typical organic anion, by basolateral membrane vesicles was enhanced when membrane vesicles were preloaded with unlabelled p-aminohippur-ate (counter-transport). Cephalosporins such as cephradine, cephalexin, and cefazolin inhibited the counter-transport of [14C]p-aminohippurate, as did unlabelled p-aminohippurate and probenecid. In contrast, cephalexin did not affect the uptake of [3H]tetraeth-ylammonium, an organic cation, by basolateral membrane vesicles. These results suggest that most cephalosporins are transported via organic anion transport systems in rat renal basolateral membranes.
Vascular effects of propofol: smooth muscle relaxation in isolated veins and arteries
Authors: Bentley G N , Gent J P , Goodchild C S
Published: April 2011

Isolated hepatic portal veins and aorta taken from the rat were used to investigate the direct action of the intravenous anaesthetic propofol. This compound is known to produce a fall in blood pressure in man and animals and it has been suggested that the hypotension may result from a direct vasodilator action on the veins and arterioles. In our experiments propofol caused a dose related decrease of potassium-induced tone in both types of blood vessel. However, the concentrations required to produce this effect in the experiments on veins were significantly lower than those required to produce similar changes in the isolated artery preparation. We conclude that this direct action may contribute towards the hypotensive effects of propofol.
Vasocontractile action of daunorubicin
Authors: Wakabayashi Ichiro , Hatake Katsuhiko , Kakishita Eizo
Published: April 2011

Daunorubicin (35·5–142 μmol L−1) induced in rat aortic strips a contraction with slow onset and a gradual development of tension on which neither phentolamine nor bromophenacyl bromide pretreatment had an effect. The contraction was not altered by removal of the endothelium but it was suppressed in calcium-free solution or by preincubation with nifedipine. These results suggest that daunorubicin directly stimulates vascular smooth muscle and induces a contractile response which is mainly dependent upon extracellular calcium.
Effect of Auranofin on Ion Transport by Rat Small Intestine
Authors: Hardcastle Jacqueline , Hardcastle P T , Kelleher Debra K
Published: April 2011

Auranofin, applied either mucosally or serosally, increased the potential difference and short-circuit current generated by stripped sheets of rat mid-intestine in a concentration-dependent manner. In-vivo auranofin induced a net fluid secretion, suggesting that the rise in electrical activity represented a stimulation of anion secretion. Removal of chloride or addition of frusemide inhibited the auranofin-induced increase in short-circuit current, indicating that chloride was the anion involved and in the case of serosal auranofin this was confirmed by direct measurement of ion fluxes. The effects of both mucosal and serosal auranofin were calcium-dependent. The gold component of the auranofin molecule is probably responsible for its secretory actions as these were mimicked by chlorauric acid. The ability of auranofin to stimulate intestinal secretion may contribute to its diarrhoeagenic action.
Pharmacokinetics of 2′,3′-Dideoxycytidine in Rats: Application to Interspecies Scale-up
Authors: Ibrahim Safaa S , Boudinot F Douglas
Published: April 2011

The effects of dose on the pharmacokinetics of 2′,3′-dideoxycytidine (DDC), a potent inhibitor of HIV replication, have been studied in rats. DDC was administered intravenously at doses of 10, 50, 100 and 200 mg kg−1. Plasma and urine drug concentrations were determined by HPLC. Non-compartmental pharmacokinetic parameters were calculated by area/moment analysis. DDC plasma concentrations declined rapidly with a terminal half-life of 0·98 ± 0·18 h (mean± s.d.). No statistically significant differences were observed in pharmacokinetic parameters between the four doses. Total, renal and nonrenal clearance values were independent of dose and averaged 1·67 ± 0·24, 0·78 ± 0·11, and 0·89 ± 0·27 L h−1 kg−1, respectively. Approximately 50% of the dose was excreted unchanged in urine. Steady state volume of distribution was also independent of dose and averaged 1·2±0·21 L kg−1. Protein binding of DDC to rat serum proteins was independent of drug concentration with the fraction of drug bound averaging 0·45 ± 0·12. Thus, the disposition pattern of DDC in the rat is independent of the administered dose even at high doses. Significant interspecies correlations were found for total, renal and non-renal clearance and steady state volume of distribution. Interspecies scaling resulted in superimposable plasma DDC concentration-time profiles from four laboratory animal species and man. Thus, plasma DDC concentrations in humans can be predicted from pharmacokinetic parameters obtained in laboratory animals.
Characteristics of hydrogel as disintegrant in solid dose technology
Authors: Fassihi A R
Published: April 2011

A comparison between a hydrogel and the disintegrants Ac-di-sol, Avicel, maize starch and Primojel has been made using theophylline as the test drug in direct compression tableting. Results indicate that the disintegrant action of the hydrogel is comparable with that of the other disintegrants used, with no adverse effect on the dissolution of theophylline from these tablets as observed by thermal analysis study. The hydrogel’s physicomechanical performance in direct compression processing appears to have no undesirable effect on the physical properties of tablets. Scanning electron micrographs of freeze-etched samples of hydrogel demonstrated its internal structure. These results strongly suggest that hydrogels have great potential as efficient disintegrants in solid dosage formulations.
Incorporation of dyes into low density lipoprotein in the presence of non-ionic surfactants
Authors: Eley J G , Halbert G W , Florence A T
Published: April 2011

The interaction of low density lipoprotein (LDL) with two model dyes in the presence or absence of non-ionic surfactants has been studied. The water soluble dye, thymol blue, only weakly interacts with LDL to cause slight increases in particle size and the interaction can be reversed on column chromatography and dialysis. The oil-soluble dye sudan III reacts strongly with LDL to produce marked changes in particle size the complex formed being stable to dialysis and gel exclusion chromatography. These interactions are not affected by the presence of surfactants. The results indicate that even small quantities of lipophilic materials will easily partition into the particle, with or without the aid of surfactants and can have a marked effect on the measured size of the particle.
Salivatory effects induced by pirenzepine, atropine, metacine and hexamethonium in preganglionar chronically denervated human parotid gland
Authors: Levin S L , Kiselman I M
Published: April 2011

Both classical (atropine) and non-traditional (pirenzepine, metacine) antagonists of the muscarinic cholinoreceptors induce, rather than block, an intense and prolonged salivary response in chronically denervated human parotid glands and thus are capable of discriminating between neuronal and aneuronal receptors. Hexamethonium (benzohexonium) a ganglion-blocking agent (0·4 mL, 2·5%) completely inhibits this paradoxical salivation to atropine, benzilylcholine (metacine) and pirenzepine in the chronic preganglionically denervated human parotid gland. The authors discuss the essence of the revealed paradoxical phenomena.
The Effect of Lactose Particle Size on the Extrusion Properties of Microcrystalline Cellulose-Lactose Mixtures
Authors: Fielden K E , Newton J M , Rowe R C
Published: April 2011

Ram extrusion has been used to assess and compare the flow characteristics and quality of wet powder masses formed from mixtures of water with microcrystalline cellulose and two different particle size samples of lactose. The force-displacement profiles can reveal poor flow properties. Steady state flow was achieved for the mixture containing fine lactose which produced an extrudate of uniform moisture content at all extrusion rates except the lowest (5 cm min−1). Increasing the lactose particle size significantly altered the extrusion properties of the formulation with forced flow predominating and high extrusion pressures observed. Formulations showing that type of extrusion are to be avoided as they produce poor quality extrudate which may be unsuitable for spheronization. Flow visualization studies showed that problems associated with such mixtures are caused by failure to maintain a constant angle of convergence during extrusion, which is essential for maintenance of steady state flow. With the mixture made with coarse lactose, the extrudate quality could be improved by extruding at high velocities, information that may be of significance in the development of formulations for large-scale production. Differences between formulations may be expressed quantitatively by plotting the apparent shear stress-shear rate relationship. The curves are modified by the particle size of lactose included in the mixtures. Such curves have implications in predicting the suitability of an extrudate, produced under particular experimental conditions, for spheronization.
The Bioavailability of a Mixed Micellar Preparation of Vitamin K1, and its Procoagulant Effect in Anticoagulated Rabbits
Authors: Winn M J , White P M , Scott A K , Pratt S K , Park B K
Published: April 2011

We have investigated the pharmacokinetics and procoagulant activity of a new, mixed-micellar preparation of vitamin K1 (MM-K) in male New Zealand White rabbits. Oral administration of MM-K alone caused a significant (P<0·01) increase in the plasma concentrations of vitamin K1 as measured by normal-phase high-performance liquid chromatography (HPLC). Maximum plasma concentrations of vitamin K1 (450 ng mL−1, range 133–824 ng mL−1) were recorded at 3·3 h (range 3–5 h), and were significantly (P < 0·05) greater than those seen after administration of an existing polyethoxylated castor oil preparation (PE-K; Konakion), which were 260 ng mL−1, range 198–390 ng mL−1 (tmax 0·8 h, range 0·4-1·2 h). AUC after MM-K (4·6 μg mL−1 h−1, range 2·1–6·3 μg mL−1) was also significantly (P < 0·05) greater than after PE-K; (1·6 μg mL−1 h−1, range 1·0–2·1 μg mL−1 h−1). However, the bioavailability of vitamin K1 after administration of MM-K was poor (9·4%), and there was considerable intra-individual variability between the concentrations of vitamin K1 recorded in the plasma samples.

Both preparations of vitamin K1 stimulated clotting factor synthesis in rabbits anticoagulated with the potent and long-acting coumarin, brodifacoum. Maximum stimulation of clotting factor synthesis by vitamin K1 after MM-K was 87%, range 44–124% (%PCA). The maximum was seen later (tmax 12 h) than after PE-K (PCA 82%, range 47–125%; tmax 5 h). However, there was considerable intra-individual variability in response to both MM-K and PE-K. Furthermore, there was no difference between the maximum PCA produced by the two preparations. It is concluded that the incorporation of vitamin K1 into bile salt micelles does not enhance either the absorption or efficacy of the vitamin after oral administration.
Reduction by acetylsalicylic acid of paracetamol-induced hepatic glutathione depletion in rats treated with 4,4‘-dichlorobiphenyl, phenobarbitone and pregnenolone-16-α-carbonitrile
Authors: van Bree L , Groot E J , de Vries J
Published: April 2011

The role of enzyme induction in the reduction by acetylsalicylic acid (ASA) of paracetamol-induced hepatic glutathione (GSH) depletion has been studied in rats. Administration of an overdose of paracetamol to control rats resulted in an appreciable decrease of GSH concentration. Pretreatment with the enzyme inducers phenobarbitone, 3-methylcholanthrene (3-MC), pregnenolone-16-α-carbonitrile (PCN) and 4,4′-dichlorobiphenyl (4,4′-DCB) significantly potentiated the paracetamol-induced depletion of GSH. Simultaneous administration of an equimolar dose of ASA resulted in a reduction of the paracetamol-induced depletion of GSH in all instances except for those rats that were not pretreated and those given 3-MC. Benorylate, the ASA ester of paracetamol, depressed rat liver GSH to levels comparable to those produced by the combination of paracetamol and ASA. ASA itself caused only minor changes in liver GSH concentrations. The results demonstrate that ASA causes a diminution of paracetamol-induced GSH depletion in rats with phenobarbitone type of enzyme induction. Inhibition of the formation of the reactive metabolite of paracetamol or reduction of the absorption rate of paracetamol seem to be unlikely as mechanisms underlying the ASA-induced effect. An ASA-mediated effect via changes of the hepatic thiol status is proposed.
RS-61756-007: a potent and selective thromboxane receptor (TP) agonist
Authors: Eglen R M , Whiting R L
Published: April 2011

The activity of RS-61756-007 (methyl-9-oxo, 15 α-hydroxy, 16-phenoxy, 17,18,19,20-tetranor prosta 4,5,13(E)trienoate, 4,5,6 (R), 8(R)) has been assessed at prostanoid receptors (DP, EP1, EP2, FP, IP and TP) in-vitro. The activity profile of RS-61756-007 resembles that of U46619, in that agonism was observed at TP and to a lesser extent at FP receptors, but there was no activity at the remaining subtypes. The actions of both RS-61756-007 and U46619 were antagonized in a similar manner by the TP antagonist SQ 29,548. We conclude that RS-61756-007 is a highly potent TP agonist.
Cefazaflur: kinetics of hydrolysis in aqueous solution, acid dissociation constant and alkaline decomposition to fluorescent products
Authors: Irwin Vincent P , Timoney Richard F
Published: April 2011

The values of the pseudo-first order hydrolysis rate constants in the pH range 1 to 10, and the pKa, were determined for cefazaflur in aqueous solution at 37°C and ionic strength 0·2 M. A fluorimetric assay, based on alkaline hydrolysis at 100°C, was also developed for this compound. The results are consistent with previously reported related properties of other monoprotic cephalosporins.