bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Environmental Humidity on the Transformation Pathway of Nitrofurantoin Modifications During Grinding and the Physicochemical Properties of Ground Products
Authors: Otsuka Makoto , Matsuda Yoshihisa
Published: April 2011

The effect of humidity on the physicochemical properties of nitrofurantoin anhydrate and monohydrate during grinding in a humidity-controlled system was investigated using X-ray diffraction analysis, IR spectroscopy, thermal analysis and scanning electron microscopy. Anhydrate and monohydrate were transformed into a noncrystalline solid and a stable monohydrate, respectively, during grinding in a closed system. During grinding in an open system, in which the humidity level of the air was controlled (5, 50 and 75% r.h.), the anhydrate absorbed moisture from the supplied air and water content was increased at 75% r.h.; thereafter the compound was transformed into monohydrate II. The anhydrate did not absorb at 5 or 50% r.h. and was transformed into a noncrystalline solid. Monohydrate I desorbed crystal water during grinding at 5% r.h. and was transformed into a noncrystalline solid. However, monohydrate I was transformed into monohydrate II at 50 and 75% r.h. without desorption of crystal water. These results suggest that the solid-state transformation of nitrofurantoin during grinding depends upon the environmental humidity.
The Transport Mechanism of an Organic Cation, Disopyramide, by Brush-border Membranes. Comparison Between Renal Cortex and Small Intestine of the Rat
Authors: Takahashi Yasushi , Itoh Tatsuya , Kobayashi Michiya , Sugawara Mitsuru , Saitoh Hiroshi , Iseki Ken , Miyazaki Katsumi , Miyazaki Shozo , Takada Masahiko , Kawashima Yoshiaki
Published: April 2011

The characteristics of disopyramide uptake in brush-border membrane vesicles isolated from rat renal cortex and small intestine were investigated. Transport of disopyramide into an osmotically reactive intravesicular space was observed with notable binding to the membrane surface. An outwardly directed H+ gradient stimulated disopyramide uptake, resulting in a transient uphill transport in both brush-border membranes. As for the renal brush-border membrane, the H+ gradient itself appeared to be the driving force for this stimulation of uptake. These findings suggest that disopyramide-H+ antiport is the mechanism of disopyramide action in renal cell membrane. The initial uptake was saturable (Km and Vmax of 680 μm and 1·25 nmol (mg protein)−1/30 s, respectively). The stimulation of disopyramide uptake by an outward H+ gradient in rat intestinal brush-border membrane was due to an interior negative H+-diffusion potential. A K+-diffusion potential (interior negative) enhanced disopyramide uptake. These results suggest that there are different mechanisms of disopyramide uptake for renal and intestinal brush-border membrane vesicles.
In-vivo Binding of (+)-[3H]PN 200–110 to Peripheral Tissues and Brain of Spontaneously Hypertensive Rats: Effect of Lacidipine
Authors: Mennini T , Taddei C , Uslenghi A , Cagnotto A , Micheli D , Trist D , Gaviraghi G , Ratti E
Published: April 2011

The time-course of dihydropyridine receptor occupancy by lacidipine and its relationship with pharmacological activity has been studied in spontaneously hypertensive rat (SHR), as measured by the inhibition of specific (+)-[3H]PN 200–110 binding in-vivo. After oral administration of doses active in reducing blood pressure, lacidipine did not show tissue target differences in respect to binding sites labelled by (+)-[3H]PN 200–110 in cerebral cortex, heart, ileum, bladder and thoracic aorta. The relative occupancy of receptors in heart 60 min after oral administration of 1 mg kg−1 lacidipine was 75%. After 12 h, when lacidipine was still effective in reducing blood pressure in SHR, a low (15%) but detectable proportion of receptors was still occupied by the drug. The percentage decrease of blood pressure was linear with the percentage of receptor occupancy obtained by different doses of lacidipine; that is, there was a close correspondence between ED25 for decrease in blood pressure (0·33 mg kg−1) and ED25 for inhibition of (+)-[3H]PN 200–110 specific binding in the heart (0·36 mg kg−1). The long-lasting effect of lacidipine on blood pressure might be explained by its selective interaction with dihydropyridine binding sites labelled in-vivo by (+)-[3H]PN 200–110.
Influence of the sterilization process on alginate dispersions
Authors: Vandenbossche Geert M R , Remon Jean-Paul
Published: April 2011

The influence of different sterilization procedures on alginate dispersions was studied by measuring viscosity and molecular weight changes. Autoclaving caused a 64% decrease in viscosity. Heating at a low temperature over several cycles was less efficient in sterilizing alginates and there was a progressive breakdown of the alginate chain over the succeeding cycles. Heating during ethylene oxide sterilization also resulted in reduced viscosity and breakdown. Membrane filtration yielded a sterile product with no significant reduction in viscosity or mol. wt.
Role of Polymorphonuclear Leucocytes and Oxygen-derived Free Radicals in the Formation of Gastric Lesions Induced by HCl/ethanol, and a Possible Mechanism of Protection by Anti-ulcer Polysaccharide
Authors: Matsumoto T , Moriguchi R , Yamada H
Published: April 2011

This study examined the role of oxygen-derived free radicals in the pathogenesis of gastric mucosal lesions induced by HCl/ethanol. Superoxide dismutase, and catalase, and their combination reduced gastric lesion formation in mice. Gastric lesions were also reduced in mice treated with cyclophosphamide or anti-neutrophils, but not in mice treated with allopurinol or desulphated-carrageenan. Cobra venom factor did not reduce lesion formation. These results suggested that oxygen-free radicals may contribute to the formation of gastric mucosal lesions induced by HCl/ethanol, and that oxygen radicals were generated from neutrophils but not from xanthine oxidase. Anti-ulcer pectic polysaccharide, bupleuran 2IIc, which was recently isolated from the roots of Bupleurum falcatum L., showed potent inhibition of HCl/ethanol-induced gastric lesions in mice. Bupleuran 2IIc seemed to scavenge hydroxyl radical effectively. It was suggested that this anti-ulcer polysaccharide may provide protection to the gastric mucosa by scavenging oxygen-free radicals.
Pharmacological Properties of β-Amyrin Palmitate, a Novel Centrally Acting Compound, Isolated from Lobelia inflata Leaves
Authors: Subarnas Anas , Tadano Takeshi , Oshima Yoshiteru , Kisara Kensuke , Ohizumi Yasushi
Published: April 2011

Effects of β-amyrin palmitate isolated from the leaves of Lobelia inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, β-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg−1). β-Amyrin palmitate (5, 10 and 20 mg kg−1) or mianserin (5, 10 and 20 mg kg−1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg−1) increased locomotor activity and potentiated methamphet-amine-induced hyperactivity. β-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg−1) and imipramine (10 and 20 mg kg−1) antagonized the reserpine-induced effect. Unlike imipramine, β-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. β-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg−1) decreased it in a dose-dependent manner. A potentiating effect of β-amyrin palmitate (5, 10 and 20 mg kg−1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg−1) but weaker than that of mianserin (2·5, 5 and 10 mg kg−1). These results suggest that β-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action. We suggest that β-amyrin palmitate has antidepressant activity with a mianserin-like profile of action.
Prediction of Cathodal Iontophoretic Transport of Various Anions Across Excised Skin from Different Vehicles Using Conductivity Measurements
Authors: Yoshida Nagahiro H , Roberts Michael S
Published: April 2011

Solute concentration, buffer concentration, applied pH and buffer constituents affect the cathodal iontophoresis of salicylate, benzoate and butyrate across excised skin. Experiments were conducted in which the iontophoretic flux of salicylate was measured across excised human skin with variations in salicylate concentration, donor solution pH, buffer concentrations and buffer consitutents. The conductivity of these solutes and of solutions described in studies on the iontophoresis of benzoate and butyrate were then measured.

The observed variations in salicylate, benzoate and butyrate fluxes across a range of conditions were found to be related to the ratio of specific conductance of the solutes in deionized distilled water to that in the buffer solution containing the solutes.

The present results suggest that conductivity of solutes in vehicle solutions is one means of predicting the iontophoretic flux of solutes from different vehicle compositions.
Comparative Evaluation of Butea frondosa and Flurbiprofen for Ocular Anti-inflammatory Activity in Rabbits
Authors: Mengi S A , Deshpande S G
Published: April 2011

The roots and leaves of the plant Butea frondosa were evaluated for ocular anti-inflammatory activity on the subacute model of ocular inflammation in rabbits.

The arkas (liquid preparations obtained by distillation of certain liquids or drugs soaked in water, using the Arka-Yantra or any other convenient modern distillation apparatus) were prepared using the roots and leaves of the plant. The arkas were formulated as gels using Pluronic F-127 (PF-127) 30% w/w as the polymer. The anti-inflammatory activity of the preparations were assessed by determining their effects on elevated intraocular pressure consequent to breakdown of blood/aqueous humour barrier. A commercial eyedrop of flurbiprofen 0.03% w/w was used to compare the ocular anti-inflammatory activity of the arkas of the plant. A marketed root arka was included in the study for comparison. The anti-inflammatory activity of the arkas formulated as gels were compared with flurbiprofen gel prepared using the same polymer. The changes in intraocular pressure were monitored at various time intervals after a single dose administration of the aqueous as well as gel formulations. In multiple dose studies the aqueous preparations were administered three times a day, while the gels were administered once a day up to day 30 and the intraocular pressure was monitored on different days post-administration.

The findings reveal statistically significant differences (P < 0.05) between the arkas of the plant and the commercial eyedrop of flurbiprofen. The arkas of the plant proved to be better than the eyedrop of flurbiprofen, while with respect to gels, the intraocular pressure monitored at various time intervals revealed no statistically significant difference (P > 0.05) between the gel formulations. However, the changes in intraocular pressure monitored on different days post-administration until day 30, demonstrated that the gel produced from B. frondosa leaves arka was superior to all the other gels with respect to the extent of reduction of elevated intraocular pressure elicited experimentally.
The Effects of Opioid Peptides on Cardiovascular Function and Sympathetic Neurotransmission in Rats
Authors: Mcintosh M A , Kane K A , Parratt J R
Published: April 2011

The haemodynamic effects of three opioid receptor agonists, with some preferential activity on δ-, μ- and κ-receptors were investigated in anaesthetized and pithed rats, and effects on sympathetic neurotransmission were also investigated in pithed rats.

In anaesthetized rats, d-Ala2-d-Leu5-enkephalin (DADLE) (a predominantly δ-receptor agonist, 10 μg kg−1), glyol (μ, 0·5 mg kg−1) and R,S-N-C2-N-methyl-3,4,dichloro-phenylacetamido-2-C3-carboxy phenylethyl-pyrrolidine (ICI 204448) (·, 0·1 mg kg−1) by intravenous administration transiently decreased heart rate from 462 ± 12 to 432 ± 14, 460 ± 12 to 448 ± 13 and 460 ± 12 to 448 ± 11 beats min−1, respectively, and mean arterial blood pressure from 142 ± 6 to 111 ± 9, 141 ± 6 to 122 ± 5 and 148 ± 7 to 121 ± 6 mmHg, respectively. The effects of DADLE, but not those of glyol or ICI 204448, were blocked by M8008, a δ-receptor antagonist. In pithed rats, none of the opioid agonists had any significant effects on heart rate or mean arterial blood pressure; however, acetylcholine significantly reduced both heart rate and mean arterial blood pressure. All three opioid agonists reduced the positive chronotropic response to thoracic (C7-T2) spinal cord stimulation in pithed rats, by 17 ± 4,30 ± 2 and 20 ± 10% for DADLE, glyol and ICI 204448, respectively. This compared with a 48 ± 15% reduction with clonidine (5 μ kg−1). This effect of DADLE was almost abolished by M8008.

It is concluded that the haemodynamic effects of the opioid agonists studied are mediated via actions on the central nervous system and that a decrease in sympathetic neurotransmission may account for, at least in part, the bradycardia produced by opioid agonists in intact anaesthetized rats. It seems that the sympathetic nervous system is unlikely to be involved in the arrhythmogenic effects of opioid peptides.
Effects of Cimetidine, Ranitidine and Omeprazole on Tolbutamide Pharmacokinetics
Authors: Toon S , Holt B L , Mullins F G P , Khan A
Published: April 2011

This randomized, four-way crossover study in 16 healthy subjects compared the effects of cimetidine 800 mg, ranitidine 300 mg and omeprazole 40 mg against placebo given daily after breakfast for seven days on the pharmacokinetics of a single oral dose of tolbutamide (500 mg) given on day 4.

Plasma tolbutamide and urinary hydroxytolbutamide and carboxytolbutamide concentrations were determined by HPLC. Ranitidine had no significant effects on tolbutamide metabolism. Cimetidine produced a 20% increase in AUC (P < 0·001) and a 14% increase in t 1/2 (P < 0·01), while omeprazole produced a 10% increase in AUC (P < 001). The effect of these agents on urinary concentrations of the tolbutamide metabolites was small.

These results do not indicate that interactions of major clinical significance occur in healthy subjects.
Effect of Policosanol on Lipofundin-induced Atherosclerotic Lesions in Rats
Authors: Noa M , Más R , De La Rosa M C , Magraner J
Published: April 2011

Policosanol is a mixture of higher aliphatic alcohols isolated from sugar cane wax, showing cholesterol-lowering effects and preventing the development of lipofundin-induced lesions in New Zealand rabbits. This study was conducted to determine whether policosanol orally administered to rats also protects against the development of lipofundin-induced atherosclerotic lesions.

Fifty four male Wistar rats were randomly distributed amongst a negative control group, a positive control group intravenously injected with lipofundin for eight days, and four experimental groups also injected with lipofundin, but orally receiving policosanol at 0·5, 2·5, 5 and 25 mg kg−1, respectively. Policosanol treatment was orally administered once-a-day for eight days, while control groups similarly received equivalent amounts of vehicle. A significant reduction of the atherosclerotic lesions in the treated animals was observed.

It is concluded that policosanol has a protective effect on lipofundin-induced aortic lesions in Wistar rats.
The Transhepatic Response to Noradrenaline in the Rabbit Liver: the Influence of Arterioportal Pressure Gradient
Authors: Browse Dominic J , Benjamin Irving S , Alexander Barry
Published: April 2011

The dose-related responses of the hepatic arterial and portal venous vascular beds to bolus administration of noradrenaline (10−10−10−4mol), injected into the hepatic artery and portal vein, were studied in the isolated dual-perfused rabbit liver at both basal and raised tone. The transhepatic ratio, defined as the ratio between the intra-arterial molar ED50 dose and the intraportal dose required to give the same arterial response, was calculated for arterial and venous responses to noradrenaline.

At basal tone, the transhepatic ratio for hepatic arterial vasoconstrictive responses was 500. Portal venous vasoconstrictive responses were similar in potency independent of injection site but differed significantly in analysis of dose-response slope and maximal response. At raised tone, the arterio-portal pressure gradient increased by 68·5 mmHg and there was a 10-fold increase in the transhepatic ratio for hepatic arterial responses, while the portal venous responses remained unchanged.

These results demonstrate that arterio-portal pressure gradient has a powerful effect on transhepatic action of noradrenaline, and suggest a pre-sinusoidal site for the generation of both hepatic arterial and portal venous vascular resistance.
Irreversible Inhibition of Rat Liver Mitochondrial MAO A and MAO B by Enantiomers of Deprenyl and α-Methylpargyline
Authors: Robinson J B , Bocchinfuso R , Khalil Amira
Published: April 2011

Using rat liver mitochondrial monoamine oxidase (MAO) A and MAO B, the possible influence of stereochemical factors upon the irreversible inhibition by propargylamine derivatives has been studied using the enantiomers of deprenyl and of α-methylpargyline.

Whether studying the inhibition of MAO A or MAO B, little difference was found among enantiomeric pairs in the first-order rate constant (k2) for formation of the enzyme inhibitor adduct. Similarly, and with the exception of (S)-d-(+)-deprenyl (k2 = 0 or an extremely low value at MAO A), the computed value of k2 for the individual enantiomers showed little variation between MAO A and MAO B.

These results suggest that inhibitor selectivity towards a particular form of the enzyme is determined predominantly at the competitive phase of the inhibition.
In-vitro and In-vivo Studies of the Diclofenac Sodium Controlled-release Matrix Tablets
Authors: Liu Cheng-Hsiung , Kao Yuh-Horng , Chen Shou-Chiung , Sokoloski Theodore D , Sheu Ming-Thau
Published: April 2011

Controlled release matrix tablets for diclofenac sodium were developed in this study.

Five matrix-tablet formulations were prepared by granulating two viscosity grades of HPMC (hydroxylpropylmethylcellulose) in varying ratios with water in the planetary mixer. The in-vitro dissolution tests indicate that all five matrix formulations prolong the release of diclofenac sodium. The main factors controlling drug release were the HPMC viscosity grade and the amount of HPMC used. The larger the amount of high viscosity grade HPMC used, the slower the resultant release rate of diclofenac sodium. There was no significant degradation of diclofenac sodium or change in drug release rate in any of the five formulations during a three-month period of stability testing. The sustained release ability of four formulations was further demonstrated in an in-vivo study in six healthy subjects.

There were in-vitro/in-vivo correlations between Cmax, AUC0–14, and the time for 50 or 80% drug to be released.
Spectroscopic Analysis of the Binding of Amylobarbitone, Secbutobarbitone, Pentobarbitone, Phenobarbitone and Quinalbarbitone to Human Serum Albumin
Authors: González-Jimènez J , Moreno F , Blanco F Garcìa
Published: April 2011

The binding of five barbiturates: amylobarbitone, secbutobarbitone, pentobarbitone, phenobarbitone and quinalbarbitone to human serum albumin (HSA) was studied by difference spectroscopy and spectro-fluorimetric titrations. There were no changes in the HSA spectral properties. Our result suggest that there are two classes of binding sites on HSA for these barbiturates. A detailed investigation of the effect of their binding to HSA by deconvoluted spectra, suggests that the interaction of barbiturate-HSA takes place principally on the subdomain IIIA of HSA.
Lack of an Effect of Madopar on the Disposition of Tolcapone and its 3-O-Methylated Metabolite in Rats
Authors: Funaki Tomoo , Onodera Hideko , Ushiyama Naomi , Tsukamoto Yuko , Tagami Chieko , Fukazawa Hideo , Kuruma Isami
Published: April 2011

The effect of Madopar (benserazide and l-dopa, 1:4) on the disposition of the new selective inhibitor of catechol-O-methyltransferase, tolcapone, in rats was investigated. There was no statistically significant difference in the pharmacokinetic parameters of tolcapone in the presence or absence of Madopar except for a change in the mean residence time after oral administration. Thus, we rejected the hypothesis that the consumption of S-adenyl-l-methionine by Madopar would change the disposition of tolcapone.

There were no statistically significant differences in the cumulative amount absorbed of drug and the absorption rate in the presence or absence of Madopar. We concluded that there was no interaction between tolcapone and Madopar.
Bioavailability and Pharmacokinetics of Sublingual Oxytocin in Male Volunteers
Authors: de Groot Akosua N J A , Vree Tom B , Hekster Yechiel A , Pesman Gerard J , Sweep Fred C G J , van Dongen Pieter J W , van Roosmalen Jos
Published: April 2011

The aim of this investigation was to assess the bioavailability and pharmacokinetics of oxytocin in six male subjects after a sublingual dose of 400 int. units (684 μg) and after an intravenous dose of 1 int. unit (1·71 μg).

After intravenous administration, the pharmacokinetic profile could be described with a two-compartment model. The distribution half-life was 0·049 ± 0·016 h, the elimination half-life was 0·33 ± 0·23 h, the total body clearance was 67·1 ± 13·4 Lh−1 and the volume of distribution was 33·2 ± 28·1 L. After sublingual administration, a poor bioavailability with a 10-fold variation between 0·007 and 0·07% was observed. The pharmacokinetic profile could be described with a one-compartment model. The lag time was subject-dependent and ranged between 0·12 and 0·30 h (40% CV). The absorption half-life was 0·45 ± 0·29 h, and the apparent elimination half-life 0·69 ± 0·26 h.

This study showed a very poor and interindividual variability in bioavailability. The sublingual route of administration with its ‘long’ lag time and ‘long’ absorption half-life would not seem a reliable route for accurate high dosing for immediate prevention of post-partum haemorrhage.
Synthesis and Antiplatelet Effects of ω-Aminoalkoxylxanthones
Authors: Lin Chun-Nan , Liou Shorong-Shii , Lai Shih-Chen , Lin Hsien-Cheng , Ko Feng-Nien , Liu Hong-Wen , Teng Che-Ming
Published: April 2011

A series of ω-aminoalkoxylxanthones were synthesized and tested in-vitro for their ability to inhibit aggregation of rabbit washed platelets and human platelet-rich plasma (PRP) induced by various inducers. Nine of these compounds showed more potent antiplatelet effects than natural norathyriol tetraacetate on collagen-induced aggregation. The various ω-aminoalkoxyl side chains of the synthesized compounds modified the antiplatelet effects. All the compounds tested in human PRP showed significant inhibition of secondary aggregation induced by adrenaline, suggesting that the antiplatelet effects of these compounds is mainly due to an inhibitory effect on thromboxane formation. These compounds at high concentration also cause vasorelaxing action in rat thoracic aorta.
Inotropic and Chronotropic Effects of 4-(4′-n-Butylaniline)-7,8-dimethoxy-5H-pyrimido[5,4–b]indole in Guinea-pig Atria
Authors: Castiella E , Frechilla D , Lasheras B , Cenarruzabeitia E , Martínez De Irujo J J , Alberdi E , Santiago E , Monge A , Villanueva A , Martinez F J , Font M
Published: April 2011

Cardiotonic effect of 4-(4′-n-butylaniline)-7,8-dimethoxy-5H-pyrimido[5,4-b)]indole (B11) was investigated in isolated cardiac tissue preparations. The action of this agent on force of contraction, beating frequency and cyclic nucleotide phosphodiesterase (PDE) activity was studied. Amrinone was used for comparison.

B11 produced concentration-dependent (5 × 10−6-1 × 10−4m) positive inotropic and positive chronotropic responses in guinea-pig atrial tissues. The potency of B11 was greater than that of amrinone. The cardiotonic effects of B11 were not modified by β-adrenoceptor blockade. Carbachol inhibited the positive inotropic effect of B11. The activity of B11 was increased in desensitized left atrial tissues. B11 inhibited the activities of PDE isoenzymes (type I, II, IV and V) from dog heart ventricle and PDE type IV from guinea-pig heart ventricle nonselectively.

It is concluded that B11 possesses potent positive inotropic activity in guinea-pig atria, and the effect is probably mediated by a non-selective inhibition of PDE activity.
QSAR Studies of Some Sulphonamidobenzophenone Oximes with Antiviral Activity
Authors: Hadjipavlou-Litina Dimitra J
Published: April 2011

A study of quantitative structure-activity relationships (QSAR) has been performed for some sulphonamidobenzophenone oximes to investigate the mechanism of their antiviral activity against polio and rhino viruses.

It has been shown that viral macromolecule synthesis could be the target of their action and that the antiviral activity of the compounds is predominantly controlled by steric factors.
Preservative Efficacy Tests in Formulated Nasal Products: Reproducibility and Factors Affecting Preservative Activity
Authors: Hodges N A , Denyer S P , Hanlon G W , Reynolds J P
Published: April 2011

Preservative efficacy tests were performed in triplicate on each of three batches of three formulated nasal spray preparations to assess the inter- and intra-batch variation in preservative performance which typically results from these procedures, and to assess the relative importance of factors influencing preservative performance in nasal products.

Tests were conducted using procedures conforming, as far as possible, to both the European and the US pharmacopoeias and the results interpreted using the performance criteria of both. Despite the adoption of practices designed to maximize reproducibility, a marked variation in the degree of microbial inactivation was observed, both within and between batches of product.

A preservative system comprising benzalkonium chloride and phenylethyl alcohol was found to be far superior to combinations of either benzalkonium chloride plus disodium edetate or potassium sorbate plus disodium edetate, both of which failed to satisfy the EP performance criteria on a number of occasions. Proposals are made for the adoption of inactivation criteria which incorporate realistic error limits reflecting the inherent problems of reproducibility of the viable counting procedures involved.
Immunopharmacological Activity of the Purified Insoluble Glucan, Zymocel, in Mice
Authors: Suzuki Tatsuya , Ohno Naohito , Chiba Norihisa , Miura Noriko N , Adachi Yoshiyuki , Yadomae Toshiro
Published: April 2011

Although it has been established that soluble glucan in fungi is important to host defence against infection, the importance of insoluble glucans is not clear. We have examined the in-vivo immunopharmacological activity of the insoluble glucan, zymocel.

Administration of zymocel increased peritoneal exudate cell number and spleen weight, and enhanced: phagocytic activity, hydrogen peroxide production, and nitric oxide production of peritoneal exudate cells; the extravascular release of Evans blue (which might reflect vascular permeability); lipopolysaccharide-triggered synthesis of tumour necrosis factor (TNF); and recovery of white blood cell number in cyclophosphamide-induced leukopenia. Zymocel also showed anti-tumour activity against sarcoma 180 in mice and also enhanced TNF synthesis and hydrogen peroxide production by macrophage-like cell line in-vitro, i.e. resulted in direct macrophage activation.

These results show that zymocel shows varied immunopharmacological activity; it is suggested that the administration of insoluble glucan induces the inflammatory response, the subsequent activation of the immune systems via the cytokine network, and direct macrophage activation.
CR 2249: a New Putative Memory Enhancer. Behavioural Studies on Learning and Memory in Rats and Mice
Authors: Garofalo Paolo , Colombo Silvia , Lanza Marco , Revel Laura , Makovec Francesco
Published: April 2011

The effects of S-4-amino-5-[4,4-dimethylcyclohexyl)amino]-5-oxopentanoic acid (CR 2249), a new entity selected from a new series of glutamic acid derivatives, has been investigated in different paradigms for screening nootropics.

CR 2249 ameliorated the memory retention deficit produced by scopolamine in step-through-type passive avoidance in rats and by electroconvulsive shock in step-down-type passive avoidance in mice. CR 2249 was also capable of improving performance in behavioural tests of learning and memory in the absence of cholinergic hypofunction or cognitive deficit. The activity was determined using different passive and active avoidance behavioural test procedures on rats. CR 2249 was active only when given 45 min before training and did not show any effect when administered immediately after the learning training or before the retention trial. No changes in the general behaviour or motor activity of the animals were observed, indicating that CR 2249 effects cannot be attributed to sensory-motor deficit. Microdialysis experiments have shown that CR 2249 significantly increased noradrenaline release in the hippocampus of freely moving rats and reduced 3,4-dihydroxyphenylglycol efflux. These effects have led us to hypothesize that CR 2249 memory effect might be mediated by a direct or indirect action on noradrenergic transmission. These behavioural results suggest that this new agent has clinical application in memory disorders.
Frequency Distribution of Candida albicans Blastospores Adhered to Mucosal Epithelial Cells In-vitro
Authors: Gorman S P , Jones D S , Mcgovern J G , Woolfson A D
Published: April 2011

Although several methods are available for examination of microbial adherence to epithelial cells, these do not distinguish between adherence of viable and non-viable micro-organisms. This study reports the use of acridine orange-stained blastospores of Candida albicans in conjunction with direct epifluorescence microscopy to determine viable (orange-fluorescing) and non-viable (green-fluorescing) blastospore adherence to buccal epithelial cells. The method was also employed to examine the effects of chlorhexidine treatment at sub-minimum inhibitory concentrations on the adherence of viable and non-viable blastospores.

There was good correlation in the assessment of blastospore viability between the direct epifluorescence microscopy technique and the standard serial dilution and plating method for viable counting, confirming the reliability of direct epifluorescence microscopy. Chlorhexidine treatment before acridine orange staining did not alter this assessment of viability. Blastospore adherence to buccal epithelial cells resulted in a similarly skewed distribution whether examined using a crystal violet stain in conjunction with light microscopy or using direct epifluorescence microscopy, therefore validating the direct epifluorescence microscopy technique for the enumeration of blastospore adherence. Chlorhexidine treatment (0.0005% v/v, 30 min) of either blastospores or buccal epithelial cells altered the distribution of adherent blastospores per epithelial cell by increasing the number of epithelial cells having no adherent blastospores. No differences in adherence were, however, observed between blastospore or epithelial cells after treatment with this agent. Examination of the adherence of viable and non-viable blastospores to buccal epithelial cells using direct epifluorescence microscopy revealed a greater adherence capacity of non-viable than viable blastospores for buccal epithelial cells. Treatment of blastospores with chlorhexidine altered the frequency distributions of viable and non-viable blastospores with lower numbers of blastospores adherent per epithelial cell. The larger reduction in adherent viable blastospores in comparison with their non-viable counterparts is, however, an important observation which might have clinical relevance.

Microbial cells adhere to epithelial cells resulting in a skewed distribution; study of this distribution gives useful information about the adherence process. Viable and non-viable components of a microbial population have different adherence capabilities and treatment of such populations with an antimicrobial agent exerting anti-adherent activity at sub-minimum inhibitory concentrations reduces the amount of adherence of these viable/non-viable components to different extents.
Bioequivalence and Generic Prescribing: An Industrial View
Authors: Pidgen Alwyn
Published: April 2011

The whole concept of bioequivalence is based upon the existence of a clear relationship between drug concentration and clinical effect.

To date there are insufficient data available in the form of publications to support this concept.

Both the pharmaceutical industry and the regulatory authorities could do more to promote this issue and publish relevant information.

The pharmaceutical industry could provide more information on concentration-effect relationships in volunteers and patients.

Upon expiry of the patent, regulators could provide estimates of the inter- and intra-subject variability in the pharmacokinetics of a drug in volunteers and patients, asessment of therapeutic windows for drugs and drug classes and their impact on bioequivalence acceptance criteria.

Current regulatory guidelines refer to rate and extent of absorption BUT there is no rate parameter which allows products to be compared for both pharmaceutical quality and safety and efficacy.
Antimicrobial Activity of Electrochemical Silver Ions in Nonionic Surfactant Solutions and in Model Dispersions
Authors: Scalzo M , Perazzi M E , Simonetti N , Cerreto F
Published: April 2011

The microbicidal effectiveness against Gram-positive and Gram-negative bacteria and Candida albicans of electrochemical silver ions in aqueous solutions containing nonionic surfactants was investigated. From the perspective of the possible use of anodic silver as a preservative in cosmetic or pharmaceutical preparations, microbicidal efficacy was also studied in oil/water model dispersions.

Surfactants and botanical extracts partially inhibited the microbicidal effectiveness of anodic silver. Nevertheless in all the experimental conditions, silver ions reduced the microbial concentration up to 4 log units of the starting inoculum in less than 6h.

The wide microbicidal spectrum and the high rate of kill of silver ions appear, therefore, attractive enough to suggest a possible utilization of anodic silver as a preserving agent.
Glibenclamide Antagonizes the Inhibitory Effect of Morphine on Gall Bladder Emptying
Authors: Patil B M , Thakker P R
Published: April 2011

Egg yolk-induced gall-bladder emptying in mice was used to investigate the effect of glibenclamide and minoxidil (ATP-dependent K+-channel modulators) on biliary tract effects of morphine.

The inhibitory effect of morphine (1–4 mg kg−l, i.p.) on egg yolk-induced gall-bladder emptying was completely blocked by pretreatment with naloxone (2 mg kg−l, i.p.) or glibenclamide (0.65 mg kg−l, i.p.) whereas, pretreatment with minoxidil (0.65 mg kg−1, i.p.) did not modify the inhibitory effect of morphine on gall-bladder emptying.

Our results suggest that biliary-tract actions of morphine are mediated through glibenclamide-sensitive K+ channels similar to those involved in the analgesic action of morphine.
Modification of Ca2+ Metabolism in the Rabbit Aorta as a Mechanism of Spasmolytic Action of Warifteine, a Bisbenzylisoquinoline Alkaloid Isolated from the Leaves of Cissampelos sympodialis Eichl. (Menispermaceae)
Authors: de Freitas M R , Côrtes S De F , Thomas G , Filho J M Barbosa
Published: April 2011

The regulation of intracellular Ca2+ as a mechanism of spasmolytic activity of a bisbenzylisoquinoline alkaloid, warifteine, isolated from the leaves of Cissampelos sympodialis, Eichl (Menispermaceae) was studied in the rabbit aorta.

Warifteine (pD'2 4.12 ± 0.09) similar to verapamil (pD'2 6.89 · 0.05) antagonized, in a noncompetitive and reversible manner, KCl-induced contractions, mediated by Ca2+ entry through voltage-operated channels. Noradrenaline-induced sustained contractions mediated by Ca2+ entry through receptor-operated channels were also inhibited by warifteine (IC50 6.03 × 10−5 m) and the standard agent sodium nitroprusside (IC50 1.9 × 10−8 m). In Ca2+-free medium, the alkaloid reduced the intracellular Ca2+-dependent transient contraction to noradrenaline by inhibiting the release of Ca2+ (IC50 2.6 × 10−5 m) from the stores and the refilling (IC50 1.9 × 10−5 m) of the intracellular stores. The standard agent, procaine, also inhibited the release of Ca2+ (IC50 3.2 × 10−5 m) but had no significant effect on Ca2+ uptake into the stores. Warifteine failed to affect intracellular Ca2+ stores sensitive to caffeine, while procaine inhibited (IC50 7.9 × 10−4 m) the release of Ca2+ from these stores.

The results indicate that warifteine may cause muscle relaxation by inhibiting Ca2+ channels and by modifying the intracellular Ca2+ stores sensitive to noradrenaline.
The Effect of Surfactant and Solid Phase Concentration on Drug Aggregates in Model Aerosol Propellent Suspensions
Authors: Bower Christopher , Washington Clive , Purewal T S
Published: April 2011

The effect of increasing solid phase concentration on the morphology and flocculation rate of model aerosol suspensions has been investigated. Suspensions of micronized salbutamol sulphate and lactose in trichlorotrifluoroethane (P113) were studied under conditions of increasing shear stress. By use of image analysis techniques, measurement of aggregate size, fractal dimension and rate of aggregation was performed. The effect of the surfactant sorbitan monooleate on morphology and flocculation rate was also studied.

Increased solid phase concentration caused an increase in the rate of aggregation and average aggregate size at a given value of shear stress. Surfactant addition retarded the aggregation rate, and caused a shift from a diffusion-limited cluster aggregation to a reaction-limited cluster aggregation mechanism. The aggregate profiles showed a corresponding change from rugged and crenellated without surfactant, to increasingly smooth and Euclidian with increasing surfactant concentration. The morphological changes were characterized by a decrease in the average boundary fractal dimension which also correlated well with the corresponding reduction in aggregation rate.
Effect of Activated Charcoal and Atropine on Absorption and/or Exsorption of Organophosphorus Compounds in Rats
Authors: Tomimaru Aki , Arimori Kazuhiko , Inotsume Nobuo , Nakano Masahiro
Published: April 2011

Effects of activated charcoal and atropine for the removal of organophosphorus compounds, which remain in the gastrointestinal tract or have already been absorbed into the systemic circulation, were investigated in rats.

Activated charcoal extensively adsorbed the organophosphates fenitrothion, tolclofos methyl, piperophos and salithion, and its immediate administration after oral ingestion of fenitrothion remarkably reduced serum fenitrothion levels, but had no effect on the serum levels of the compound which had been absorbed from the gastrointestinal tract. Thus, all of the organophosphorus compounds were poorly exsorbed (0.002-0.39% of the dose in 120 min) from the blood into the intestinal lumen probably due to their extensive protein binding and large distribution volumes. Atropine inhibited absorption of fenitrothion in the perfusion in-situ and also delayed the absorption of the compound in-vivo, but had no significant effect on exsorption of fenitrothion. The serum fenitrothion levels on treatment with both atropine and charcoal significantly decreased compared with those of the control. We conclude that, oral activated charcoal will not be able to enhance the elimination of organophosphorus compounds which have already been absorbed into the systemic circulation, but constitute a useful method for the removal of the compounds remaining in the gastrointestinal tract because of its excellent adsorptive capacity.
Mechanism of Action of p-Chlorobiphenyl on the Inhibition of Platelet Aggregation
Authors: Ko Feng-Nien , Yeh Ling-Jau , Liang Hsiu-Chuan , Kuo Sheng-Chu , Teng Che-Ming
Published: April 2011

p-Chlorobiphenyl (1–50 μm) concentration-dependently inhibited the aggregation and release reaction of rabbit washed platelets induced by arachidonic acid and collagen, but not those induced by platelet-activating factor (PAF), U46619 and thrombin. The IC50 values of p-chlorobiphenyl on the arachidonic acid and collagen-induced platelet aggregation were 2.9 ± 0.5 and 12.8 ± 2.3 μm, respectively. The formation of both platelet thromboxane B2 and prostaglandin D2 caused by arachidonic acid was inhibited by p-chlorobiphenyl concentration-dependently. In myo-[3H]inositol-labeled and fura-2-loaded platelets, [3H]inositol monophosphate generation and the rise in intracellular Ca2+ stimulated by arachidonic acid were inhibited by p-chlorobiphenyl. In human platelet-rich plasma, p-chlorobiphenyl and indomethacin prevented the secondary aggregation and blocked ATP release from platelets induced by adenosine 5′-diphosphate and adrenaline without affecting the primary aggregation.

It is concluded that p-chlorobiphenyl may be a cyclo-oxygenase inhibitor and its antiplatelet action is mainly due to the inhibition of thromboxane formation.
Antithrombotic Activity of a 2-kDa Heparin Fragment in an Experimental Model of Carotid Artery Thrombosis in Rats
Authors: Guarini Salvatore , Bazzani Carla , Botticelli Annibale , Balugani Alessandro , Bertolini Alfio
Published: April 2011

The antithrombotic activity of a 2-kDa heparin fragment was studied in a rat model of common carotid artery thrombosis that causes a completely occlusive thrombus with cessation of the blood flow within 10–15 min.

The compound reduced thrombus formation in a dose-dependent manner, starting from an intravenous dose of 5 mg kg−1. A dose of 20 mg kg−1 completely prevented thrombus formation and apparently induced the almost complete lysis of the already formed occlusive thrombus. At none of the doses used did the compound cause increased bleeding or the formation of haematomas.

The present results indicate that low molecular weight heparins, which have an established, highly beneficial effect in venous thromboembolism, are also highly effective in an animal model of arterial thrombosis.
Inhibition of Lipid Peroxidation by Sesquiterpenoid in Heterotheca inuloides
Authors: Haraguchi Hiroyuki , Saito Takashi , Ishikawa Harumi , Sanchez Yolanda , Ogura Tetsuya , Kubo Isao
Published: April 2011

A sesquiterpenoid, 7-hydroxy-3,4-dihydrocadalin, isolated from a Mexican medicinal plant Heterotheca inuloides was evaluated as an antioxidant.

This sesquiterpenoid inhibited mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH. Furthermore, 7-hydroxy-3,4-dihydrocadalin protected red cells against oxidative haemolysis.

This sesquiterpene was thus shown to be effective in protecting biological systems against oxidative stresses.
Improved Stereospecific Syntheses of Novel 1-alkyl-3-benzoyl-4-hydroxy-4-phenylpiperidines
Authors: Jaffar Mohammed , Upton Christopher
Published: April 2011

The stereoselective synthesis of conformationally restricted 1-alkyl-3-benzoyl-4-hydroxy-4-phenylpiperidine hydrochlorides via the Mannich reaction followed by an intramolecular aldol condensation is reported. The compounds were evaluated by 1H NMR and 13C NMR techniques.
Decomposition Kinetics of Cisplatin in Human Biological Fluids
Authors: Nagai N , Okuda R , Kinoshita M , Ogata H
Published: April 2011

Cisplatin is metabolized to high- and low-molecular mass complexes by exchanging of one or both chloride ligands with nucleophilic species. The decomposition of cisplatin and the formation of its metabolites in human biological fluids was investigated in-vitro.

In nucleophile-free medium, cisplatin was decomposed by a reversible chloride ligand exchange reaction, which was dependent upon both chloride ion concentration and medium pH. The effect of pH was observed in the second-order rate constant for cisplatin re-formation, which was far smaller in neutral and alkaline media than in acidic media. In the medium containing nucleophilic species (glutathione, human albumin and globulin), cisplatin was irreversibly decomposed according to apparent first-order kinetics. The linear relationship between apparent decomposition rate constant and concentration of nucleophilic species suggested that nucleophilic species in biological fluids might react with cisplatin directly. Both high- and low-molecular mass metabolites were formed in human plasma and ascites; however, only a low-molecular mass metabolite was produced in urine. The faster decomposition of cisplatin and the greater ratio of fixed and mobile metabolites formed in plasma were mainly attributed to higher albumin concentration in plasma than in ascites and urine.

The in-vitro decomposition of unchanged cisplatin and formation of high- and low-molecular mass metabolites in human biological fluids were simultaneously evaluated according to the kinetic model which combined both pathways via hydrolysis and by the direct reaction process with nucleophilic species.
Involvement of a Cytochrome P450 System in Microsomal Debromination of α-(Bromisovaleryl)urea
Authors: Oka Koji , Kitamurax Shigeyuki , Tatsumi Kiyoshi
Published: April 2011

The reductive debromination of a hypnotic, (α-bromisovaleryl)urea to (3-methylbutyryl)urea by rat liver microsomes was studied.

Pretreatment of rats with cytochrome P450 inducers such as phenobarbitone, 3-methylcholanthrene, acetone and pregnenolone-16α-carbonitrile enhanced the debromination of (α-bromisovaleryl)urea by liver microsomes. Microsomal debromination was inhibited by cytochrome P450 inhibitors such as metyrapone, α-naphthoflavone, SKF 525-A and carbon monoxide. Microsomal debromination was enhanced by addition of NADPH-cytochrome P450 reductase and inhibited by addition of an antibody against the flavo enzyme to the liver microsomes. A reconstituted cytochrome P450 system containing NADPH-cytochrome P450 reductase, and cytochrome P450 1A1 or P450 2B1 exhibited debrominating activity toward the hypnotic.

These results indicated that a cytochrome P450 system plays an essential role in the microsomal debromination of (α-bromisovaleryl)urea.
Screening for Cytochrome P450 3A in Man: Studies with Midazolam and Nifedipine
Authors: Yeates R A , Scharpf F , Laufen H , Zimmermann T
Published: April 2011

This report describes work directed towards the development of a screening technique for cytochrome P450 3A activity which should be valid for a variety of drugs metabolized by this enzyme.

A significant correlation (P < 001) was found between the ratio of the plasma concentration of nifedipine to that of its oxidized metabolite and the area under the time curve for the plasma concentration of midazolam.

It is suggested that the nifedipine: metabolite ratio might have general predictive value for the metabolism of orally administered cytochrome P450 3A substrates.