bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction Between Fibronectin-bearing Surfaces and Bacillus Calmette-Guérin (BCG) or Gelatin Microparticles
Authors: Lou Y , Olson W P , Tian X X , Klegerman M E , Groves M J
Published: April 2011

Gelatin, prepared commercially by degradation of animal collagen, was studied to see whether it had an affinity for fibronectin, which has a known affinity for collagen, and whether gelatin-based drugs could be used to target fibronectin-excreting tumours.

Bacillus Calmette-Guérin (BCG) vaccine, an attenuated strain of Mycobacterium bovis, is currently the most effective treatment for superficial transitional cell carcinoma of the bladder. The living cells of the BCG vaccine associate with the fibronectin-bearing surfaces of the tumour.

Using a multi-well culture plate technique, gelatin microparticles were shown to be adsorbed onto murine S180 sarcoma cells and this reaction was substantially inhibited by the addition of human plasma fibronectin.

The avidities of various BCG substrains and gelatin microparticles for glass-bound fibronectin were measured and the association constants determined. The gelatin microparticles associated with the fibronectin with equal avidity as the BCG cells.

The results suggest that this model system may allow the investigation of gelatin-based drug delivery devices capable of targeting fibronectin-bearing surfaces associated with some tumours.
Calorimetric Evaluation of Hydration of Cholestyramine
Authors: Joshi H N , Wilson T D
Published: April 2011

We have investigated the mechanism of hydration of cholestyramine, a water-insoluble resin used pharmaceutically.

Two types of water of hydration (freezing and non-freezing) and the amounts of heat evolved or absorbed during the hydration of cholestyramine were determined. From differential scanning calorimetry, 0·57 g water was observed to be tightly bound per gram of resin (non-freezing water). The hydration of dry cholestyramine was found to be exothermic. The heats of hydration of cholestyramine with chloride or nitrate counter-anions were found to be −6·05 and −3·46 cal g−1, respectively. Some of the partially hydrated cholestyramine samples showed absorption of heat during hydration.

The data generated in the study were utilized to better understand the mechanism of hydration and swelling of cholestyramine.
Anticonvulsant Activity of Phenytoin-lipid Conjugates, a New Class of Phenytoin Prodrugs
Authors: Scriba Gerhard K E , Lambert Didier M , Poupaert Jacques H
Published: April 2011

The anticonvulsant activity of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxy-methylphenytoin to dimyristoylglycerides via a succinidyl linkage, to 2-(1,3-dimyristoylglyceryl)butyric acid and to 3-myristoyl-2-myristoylmethylpropionic acid was evaluated in the maximal electroshock (MES) test and the seizure threshold test with subcutaneous pentetrazol.

The phenytoin-lipid conjugates were less active than the parent drug in the MES test after intraperitoneal administration as suspensions, but exhibited comparable activity when injected as a solution in dimethysulphoxide. They also protected mice from MES-induced seizures following oral administration of aqueous suspensions of the compounds or when incorporated into emulsions. The anticonvulsant activity could be correlated to in-vitro pancreatic lipase-mediated hydrolysis. The bis-deacyl derivatives were at least as active but in some cases also more toxic than phenytoin. Oral administration of two of the lipid conjugates resulted in a faster onset of the anticonvulsant activity compared with the administration of an equimolar dose of phenytoin itself. All compounds were inactive in the subcutaneous pentetrazol test.

It is concluded that the lipids act as prodrugs of phenytoin, which is generated by lipolysis upon oral administration.
Mechanism for Drug Absorption from Rat-liver Surface Membrane: Effect of Dose and Transport Inhibitors on the Pharmacokinetics of Phenol Red
Authors: Nishida Koyo , Sato Norihito , Sasaki Hitoshi , Nakamura Junzo
Published: April 2011

We examined the effect of dose and transport inhibitors on the pharmacokinetics of phenol red as a model drug after application to rat liver surface in-vivo, employing a cylindrical glass cell (i.d. 9 mm, area 0·64 cm2), to elucidate the mechanism for drug absorption from liver surface membrane.

Absorption ratios of phenol red in 6 h were determined to be 91·1, 91·8 and 89·9% at a dose of 0·3, 1 and 3 mg, respectively. The AUC value for plasma concentration profile of phenol red was proportional to the dose. It is thus suggested that the absorption process of phenol red from rat liver surface does not approach saturability. The time course of the remaining amount of phenol red in the glass cell obeyed first-order kinetics at a dose of 0·3 mg, and its rate constant Ka was calculated to be 0·0069 min−1. Moreover, no significant difference was seen in the Ka value within the dose range of 0·3-3 mg, which was estimated by curve fitting of the plasma concentration profile of phenol red after application to rat liver surface in the two-compartment model with first-order absorption. 2,4-Dinitrophenol (0·3 mg) and probenecid (0·5 and 1 mg), inhibitors of metabolic energy and anion transport, respectively, had no significant effect on the pharmacokinetics of phenol red after application to rat liver surface.

These data demonstrate that a specific transport mechanism such as active transport is not involved in phenol red absorption from rat liver surface membrane.
Phenyl-substituted Normethadones: Synthesis and Pharmacology
Authors: Mbela T K N , Poupaert J H , Cumps J , Moussebois C , Haemers A , Borloo M , Dumont P
Published: April 2011

Phenyl-substituted normethadone derivatives were synthesized and their affinity (IC50) for opioid receptors was determined by displacement of the specific binding sites of [3H]sufentanyl on rat brain preparations.

Substitution resulted in a decrease of affinity in-vitro.

These results suggest that normethadone-like compounds may interact with the P subsite of the μ-opioid receptor and that the P subsite has a well-defined cavity shape of stringent dimensions.
The Peristaltic Reflex in the Rat Ileum: Evidence for Functional μ- and δ-Opiate Receptors
Authors: Coupar Ian M
Published: April 2011

The potency order of opiate agonists at decreasing the rate of peristalsis in the rat isolated ileum was: difenoxin > loperamide > DADLE (d-Ala2-d-Leu5-enkephalin) > morphine > DSLET (d-Ser2, Leu5-Thr6-enkephalin). U-50488 (trans 3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl) cyclohexyl) benzeneacet-amide methane sulphonate) was inactive at 300 nm. Naloxone (400 nm) caused a significant 1·52-fold increase in the rate of peristaltic contractions and inhibited the effects of the active opiate agonists. The apparent pA2 values of naloxone were similar using difenoxin, loperamide and morphine as agonists, but the value was slightly, though significantly lower when DADLE was the agonist.

It is suggested that the previously identified δ-opiate receptors of the rat small intestine have a functional role in suppressing the peristaltic reflex. The same response is subserved by μ-opiate receptors and either of these opiate-receptor subtypes could be activated by endogenous enkephalins.
Dihydroetorphine is a μ-Receptor-selective Ligand
Authors: Wang Dan-Xin , Lu Xin-Qiang , Qin Bo-Yi
Published: April 2011

The selectivity to opioid receptors of dihydroetorphine, a potent analgesic with only mild physical dependence, was investigated using radioligand binding assay and its analgesic activity in mice determined.

The relative affinity ratio of dihydroetorphine to μ-, δ- and κ- opioid receptors was 333:1:1. The analgesic effect of intracerebro-ventricular injection in mice could be antagonized by the μ-antagonist β-funaltrexamine but could not be antagonized by δ- and κ-selective antagonists naltrindole and nor-binaltorphimine.

We conclude that dihydroetorphine is a selective ligand for the μ-opioid receptor.
Gel Chromatographic Analysis of Cyclosporin and Its Metabolites in Human Blood Compartments
Authors: Kadobayashi M , Yamamoto K , Takahara S , Okuyama A , Takashima N , Sawada M , Yanaihara C , Kurokawa N
Published: April 2011

Gel chromatography combined with specific and non-specific cyclosporin radioimmunoassays was adopted for quantitative analysis of cyclosporin and metabolites in free and protein-bound forms in blood compartments of kidney transplant patients. The analytical method was proved to be useful for the purpose, although plasma protein-bound forms of neither cyclosporin nor metabolites could be quantitated in the system. The present study also provided, by gel chromatographic analysis, additional examples to prove that concentrations of cyclosporin metabolites in blood compartments may not be deduced or inferred simply from those of cyclosporin.
Effect of Sodium Naproxen on Inflammatory Response Induced by Anterior Chamber Paracentesis in the Rabbit
Authors: Bucolo Claudio , Spadaro Angelo
Published: April 2011

This study evaluated the effect of sodium naproxen (a reversible competitive inhibitor of cyclo-oxygenase) and phenylephrine (a mydriatic α-adrenergic agent) eye drops in maintaining atropine mydriasis in the rabbit after paracentesis. Moreover, to assess the influence of these treatments on vascular and cellular inflammatory responses in the rabbit eye, several biochemical parameters were considered.

Anterior chamber paracentesis significantly reduced atropine-induced mydriasis and a parallel elevation of proteins, polymorphonuclear leucocytes (PMNs), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels in the secondary aqueous humour (obtained 120 min later) was observed. A significant increase in PMNs in the aqueous humour and a parallel increase in myeloperoxidase activity, a measure of PMN infiltration, in the iris-ciliary body were detected. Atropine-induced mydriasis was maintained in rabbits treated with either sodium naproxen or phenylephrine eye drops. However, only in the former group were the inflammatory parameters significantly reduced, with the exception of aqueous LTB4 levels.

The inhibition of the protein influx in the aqueous humour and of the miosis produced by sodium naproxen can be related to the high drug levels in the aqueous humour that were effective in inhibiting the cyclo-oxygenase pathway of arachidonic acid metabolism, whereas the effects on PMN infiltration appear to be independent of significant release of the potent chemotactic agent LTB4, synthesized via the 5-lipoxygenase pathway.
The Transmucosal Absorption of Recombinant Human Interferon-α B/D Hybrid in the Rat and Rabbit
Authors: Bayley Deborah , Temple Cathy , Clay Val , Steward Alan , Lowther Nicholas
Published: April 2011

For therapeutic proteins such as interferon-α B/D, a non-parenteral route of delivery is desirable. Possible sites of administration include the various regions of the gastrointestinal tract and airways, and this paper reports the bioavailability of interferon-α B/D via these routes in the rat and rabbit.

Apart from the stomach, detectable levels of interferon-α B/D in the serum were achieved via all routes. Bioavailabilities were less than 1%, except from the lung (6·8% in the rat) and nasal cavity (2·9% in the rabbit). Absorption from the gastrointestinal tract was similar for both species, but in the nasal cavity of the rabbit was sixfold that of the rat, and in the lung of the rat was tenfold that in the rabbit. Absorption from all routes, except the buccal cavity, resulted in detectable biochemical changes in the liver of the rabbit.

Comparison with reports from other groups show differences in the extent of absorption of interferon-α B/D and of natural or homologous recombinant interferon-α. The non-parenteral delivery of biochemically active amounts of interferon-α B/D is thus demonstrated.
The Influence of Uptake from the Gastrointestinal Tract and First-pass Effect on Oral Bioavailability of (Z)-alkyloxyimino Penicillins
Authors: Mizen Linda , Berry Valerie , Woodnutt Gary
Published: April 2011

We have investigated the contribution of uptake from the gastrointestinal tract and first-pass effect to the poor oral bioavailability of a series of (Z) -alkyloxyimino penicillins in mice.

Investigative studies in gut sacs and perfused small intestine demonstrated that these penicillins were able to pass across the mucosal epithelium although to a lesser extent than amoxycillin and cyclacillin, both of which exhibit excellent oral bioavailability in man and animals. In the jejunal gut sacs the mucosal to serosal flux for BRL 44154 was approximately half that of amoxycillin and four times less than that of cyclacillin, and for all, uptake was pH dependent. The serosal to mucosal fluxes were however similar for these compounds and significantly lower than mucosal to serosal fluxes, suggesting involvement of carrier mechanisms in uptake from the mucosal surface. The order of results for the alkyloxyimino penicillins paralleled that observed for oral bioavailability in the mouse.

For the alkyloxyimino penicillins, between 5·5 and 9·9% was taken up from the perfused intestine, values which were significantly less than those for amoxycillin (13·2%) and cyclacillin (33·3%). However, uptake was concentration-dependent for BRL 44154 as it was for amoxycillin, thus confirming the possible use of carrier mechanisms in absorption.

These observations suggest that the poor peripheral blood concentrations of the alkyloxyimino penicillins achieved after oral dosing were not a consequence of the inability of the compounds to cross the mucosal epithelium. The biliary clearance of the alkyloxyimino penicillins was, however, considerably greater than for amoxycillin and cyclacillin, a finding which may well have been a contributory factor to the comparatively low peripheral concentrations of BRL 44154 and its analogues achieved after oral administration.
Differential Relaxant Responses of Guinea-pig Lung Strips and Bronchial Rings to Sodium Nitroprusside: A Mechanism Independent of cGMP Formation
Authors: Fred Wong W S , Roman Carlos R , Fleisch Jerome H
Published: April 2011

The biochemical mechanism subserving smooth muscle relaxant effects of sodium nitroprusside was examined on U46619, 9, 11-dideoxy-9α, 11α-methanoepoxy PGF2α, precontracted guinea-pig lung strips and hilar bronchial rings.

Lung strips were resistant to the relaxant action of sodium nitroprusside or sodium nitrite (NaNO2), whereas they markedly relaxed to 8-bromo-cyclic GMP (8-Br-cGMP), a membrane permeable analogue of cGMP. Precontracted bronchial rings completely relaxed to sodium nitroprusside, NaNO2, or 8-Br-cGMP in a concentration-dependent manner. Sodium nitroprusside (10 μm) substantially raised tissue cGMP level in lung strips. Conversely, sodium nitroprusside had no detectable effect on cGMP levels in bronchial rings. In the presence of 10 μm dipyridamole, an agent which preferentially inhibits cGMP-specific phosphodiesterase, cGMP levels in lung strips treated with sodium nitroprusside was significantly enhanced, but sodium nitroprusside demonstrated no relaxant effect on the preparations. However, dipyridamole potentiated sodium nitroprusside-induced precontracted bronchial ring relaxation without affecting the bronchial tissue cGMP level. In the presence of 10 μm LY83583 (6-anilino-5,8-quinoline-dione), a specific cGMP concentration-lowering agent, sodium nitroprusside-mediated elevation of cGMP level in lung strips was significantly reduced with no effect on the functional response. LY83583 demonstrated no inhibitory effect on either relaxation or cGMP level in bronchial rings treated with sodium nitroprusside.

Our results suggest that precontracted smooth muscle in lung strips and in hilar bronchi respond distinctly to sodium nitroprusside. Furthermore, sodium nitroprusside mediates bronchial smooth muscle relaxation by mechanisms unrelated to cGMP.
Pharmacological Properties of 403U76, a New Chemical Class of 5-Hydroxytryptamine- and Noradrenaline-reuptake Inhibitor
Authors: Ferris R M , Brieaddy L , Mehta N , Hollingsworth E , Rigdon G , Wang C , Soroko F , Wastila W , Cooper B
Published: April 2011

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene-methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats.

The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment.

Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.
Evaluation of In-vivo Transdermal Absorption of Cyclosporin with Absorption Enhancer Using Intradermal Microdialysis in Rats
Authors: Nakashima Mikiro , Zhao Mei Feng , Ohya Hisami , Sakurai Masaharu , Sasaki Hitoshi , Matsuyama Kenji , Ichikawa Masataka
Published: April 2011

The purpose of this study was to evaluate the effect of absorption enhancer on in-vivo transdermal absorption of cyclosporin using intradermal microdialysis in rats. Cyclosporin oily solutions (0.5, 2, 8% w/v) were prepared from Sandimmun (10% w/v oily oral preparation of cyclosporin) by diluting with olive oil. 1-[2-(Decylthio)ethyl]azacyclopentan-2-one (HPE-101) and glycerin were added to the cyclosporin formulation as an absorption enhancer at various concentrations between 1 and 20%. These formulations were applied to the shaved abdomen of rats treated with intradermal microdialysis at a flow rate of 2.5 μL min−1 for 6 h.

Cyclosporin was immediately detected and attained a plateau in the dermal dialysate after topical application of cyclosporin oily solution alone. Cyclosporin levels in the dialysate increased with increasing cyclosporin concentrations in the formulation from 0.5 to 8% (w/v). HPE-101 did not influence cyclosporin absorption at concentrations less than 6% (w/v). Addition of 10% (w/v) HPE-101 significantly enhanced an apparent absorption rate of cyclosporin by 4.9 times. However, 20% (w/v) HPE-101 did not show the enhancing activity. On the other hand, addition of glycerin at concentrations of 6, 10, and 20% (v/v) significantly enhanced an apparent absorption rate of cyclosporin by 3.0, 64, and 6.9 times, respectively. The time lag for cyclosporin absorption was less than 0.21 h in all tested cases.

This microdialysis study shows that glycerin is a suitable enhancer for improving the in-vivo cyclosporin absorption from the skin.
Effect of the Hydroalcoholic Extract of Rauwolfia ligustrina on Smooth and Cardiac Muscles In-vitro
Authors: De Medeiros Cleane L Costa , Calixto João B
Published: April 2011

The actions of the hydroalcoholic extract (HE) of Rauwolfia ligustrina (the whole plant) on agonist-induced contractions were analysed in the rat uterus and guinea-pig ileum and trachea, and also in rat atrium contracting spontaneously in-vitro.

The HE (100–400 μg mL−1) caused concentration-dependent rightward shifts of the concentration-response curves and reduced the maximal contraction induced by oxytocin, bradykinin, angiotensin II, prostaglandin F2α and acetylcholine in the rat uterus. The calculated mean IC50 values were: 300, 147, 158, 197 and 105 μg mL−1, respectively. In the guinea-pig ileum the HE also caused graded displacement to the right of the concentration—response curves for bradykinin, histamine and carbachol, associated with pronounced inhibition of the agonist-induced maximal contractions. The calculated mean IC50 values were 165, 134 and 241 μg mL−1, respectively. The HE (100–3000 μg mL−1) caused graded relaxation (IC50 of 271 μg mL−1) of strips of guinea-pig trachea precontracted with carbachol (0.2 μM). This effect was not infuenced by propranolol (1 μM), 3-isobutyl-1-methylxanthine (1 μM) or methylene blue (10 μM), but was significantly potentiated (1.5-to 3-fold) by indomethacin (3 μM) and forskolin (1 nM). In addition, NG-monomethyl-L-arginine (L-NMMA, 100 nM) significantly reduced the HE-induced maximal relaxation, while indomethacin (3 μM) potentiated the HE response. Finally, the HE caused a concentration-dependent and long-lasting inotropic effect in the rat right atrium, contracting spontaneously with a mean EC50 value of 409 μg mL−1.

It is suggested that the effects of the HE of R. ligustrina on smooth and cardiac muscles ‘in-vitro’ may result from its ability to interact, at least partially, with the cAMP pathway.
Characteristics of Shed Snake Skin Permeability to Indomethacin and Fatty Alcohols
Authors: Kuramoto M , Tanaka T , Makita H , Nakamura Y , Yata N
Published: April 2011

To investigate the utilities of a shed snake skin as a model membrane for preclinical studies of transdermal drug delivery, the flux of indomethacin was determined under various conditions by using a diffusion cell. The flux of fatty alcohols was determined and compared with that in human skin reported in references. The esterase activity of shed snake skin was also determined.

It was found that the flux of indomethacin decreased with an increase of pH and the amount of ethanol in a vehicle. The flux of indomethacin increased by the addition of Azone, N-methyl−2−pyrroridone and N,N-dimethyl-m-toluamide in the cream.

The flux of fatty alcohols in shed snake skin was greater than that reported in human skin, and shed snake skin had similar esterase activity to human skin.
Kinetic Studies of N-Allenic Analogues of Tryptamine as Monoamine Oxidase Inhibitors
Authors: Perez V , Marco J L , Fernandez-Alvarez E , Unzeta M
Published: April 2011

A series of N-allenic analogues of tryptamine in which the side chain is located at the 2 position of the indole ring, but which differed in the ring and side-chain nitrogen substituents, were assayed kinetically as MAO A and MAO B inhibitors.

All the compounds studied were mechanism-based inhibitors. The kinetic constants of each inhibition step Ki and ki, were determined for both MAO A and B. The data obtained indicated that these allenic derivatives show a greater selectivity and potency towards MAO A as inhibitors than the corresponding acetylenic derivatives.
7−Ethoxy−3,4−dimethylcoumarin: A Substrate for a Cytochrome p450-mediated Mono-oxygenase Activity that is Highly Induced by Phenobarbitone and β-Naphthoflavone
Authors: Giurnazi Ali Mansour , Garle Michael J , Lal Kishan , Fry Jeffrey R
Published: April 2011

The O-dealkylation of 7−ethoxy−3,4−dimethylcournarin in rat liver microsomes was catalysed in a typical cytochrome P450−mediated reaction as judged by cofactor requirement and inhibition criteria, and displayed monophasic Michaelis-Menten kinetics. When measured at low substrate concentration, this activity was highly inducible by treatment with phenobarbitone or β-naphthoflavone (44−and 78−fold induction, respectively). These data indicate the potential usefulness of this activity as a probe for P4501A1−and P4502B-mediated activities. The O-dealkylation of 7−methoxy-and 7−propoxy−3,4−dimethylcoumarin were much less inducible.
Inhibitory Effect of Pentobarbital on Biliary Excretion of Diclofenac in a Rat Liver Perfusion System
Authors: Fukuyama Takako , Yamaoka Kiyoshi , Tabata Kenji , Nakagawa Terumichi
Published: April 2011

The effect of pentobarbital on the biliary excretion of diclofenac was investigated in a rat liver perfusion system following a pulse input of the drug.

Without albumin in the perfusate, a trace amount of diclofenac was detected in the outflow from the liver (< 0.1%). The total biliary excretion of diclofenac (intact diclofenac plus its glucuronide) decreased from 23.8% (diclofenac 6.01, glucuronide 17.8%) to 16.3% (diclofenac 5.09, glucuronide 11.2%) with an increase in the perfusate concentration of pentobarbital from 0 to 2.5 μg mL−1. At pentobarbital concentrations exceeding 2.5 μg mL−1, the biliary excretion of diclofenac and its glucuronide (14% total diclofenac) was not reduced further. The mean local excretion times of both diclofenac and its glucuronide were approximately 17 min and were unchanged at all pentobarbital concentrations tested. The ratios of biliary excreted diclofenac and its glucuronide to total diclofenac were 22 and 78%, respectively, and these values were virtually constant at all concentrations of pentobarbital in the perfusate.

These results suggest that the glucuronidation of diclofenac and the biliary excretion of its glucuronide are rapid processes and that pentobarbital blocks a step before glucuronidation.
Interaction between Fenbendazole and Piperonyl Butoxide: Pharmacokinetic and Pharmacodynamic Implications
Authors: Benchaoui H A , Mckellar Q A
Published: April 2011

The effect of the cytochrome P450 inhibitor, piperonyl butoxide on the pharmacokinetics and anthelmintic efficacy of the benzimidazole compound fenbendazole was studied in sheep and goats.

Pretreatment of goats with the inhibitor caused a greater than three-fold increase in the relative bioavailability of fenbendazole and fenbendazole sulphoxide. A pharmacokinetic dose titration study was carried out in sheep with fenbendazole (5 mg kg−1) and piperonyl butoxide administered orally at 0, 15, 31, 63, 125 and 250 mg kg−1. The AUC of fenbendazole and the sulphoxide were significantly increased when fenbendazole was co-administered with piperonyl butoxide at dose rates equal to or higher than 31 mg kg−1. Peak plasma concentrations (Cmax) and mean residence time (MRT) were also significantly increased.

The efficacy of the combination was assessed in sheep against two species of benzimidazole-resistant abomasal nematodes; Ostertagia circumcincta and Haemonchus contortus. The percentage reduction in the total number of O. circumcincta worms was 7.9% (fenbendazole) and 97.8% (fenbendazole-piperonyl butoxide). For H. contortus, the percentage reduction was 84.8% (fenbendazole) and 99.0% (fenbendazole-piperonyl butoxide).

The in-vitro S-oxidation of fenbendazole and fenbendazole sulphoxide was studied using microsomal preparations from rat liver. Piperonyl butoxide inhibited significantly the sulphoxidation and sulphonation of fenbendazole.

It was concluded that piperonyl butoxide inhibited the oxidative conversion of fenbendazole into inactive metabolites and this resulted in a potentiated anthelmintic action.
Antidiarrhoeal Activity of New Thiazolidinones Related to Loperamide
Authors: Diurno M V , Izzo A A , Mazzoni O , Bolognese A , Capasso F
Published: April 2011

A series of thiazolidinones related to loperamide was synthesized and evaluated for antidiarrhoeal activity in mice, using the castor oil test.

Of five compounds tested, antidiarrhoeal activity was found only for 2−(p-nitrophenyl)−3−{3−[(4−(p-chloro-phenyl)-4−hydroxy)piperidino]ethyl}-1,3−thiazolidin−4−one. The compound was less active than loperamide (ED50 values = 48.7 (24.8−95.6) and 0.91 (0.24−3.40) mg kg−1, respectively), but was also less toxic (LD50 values = 745.9 (545.2−929.8) and 108.9 (85.5−138.7) mg kg−1, respectively). Its antidiarrhoeal activity was counteracted by naloxone.

Our results support the hypothesis that this compound, like loperamide, is an opiate-receptor agonist.
Comparative Cardiovascular Effects of the Angiotensin II Type 1 Receptor Antagonists ZD 7155 and Losartan in the Rat
Authors: Junggren Inga-Lill , Zhao Xiaohe , Sun Xiangying , Hedner Thomas
Published: April 2011

Binding experiments show that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. In this study this novel substance was studied in normotensive and hypertensive rats.

The relative potency and duration of the antihypertensive effects of ZD 7155 were compared with those of the reference substance, losartan. The inhibitory effects of both compounds on angiotensin II-induced pressor actions were studied in the conscious normotensive Sprague-Dawley (SD) rat and in the conscious, spontaneously hypertensive rat (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intraarterial recording. Angiotensin II infusion was administered intravenously in the dose range 53.3 ng—12.8 μg kg−1 min−1 to the conscious rats. ZD 7155 was administered in a bolus dose of 1.082 μmol kg−1 (0.51 mg kg−1) and losartan in bolus doses of 2.165 and 6.495 μmol kg−1 (1.0 and 3.0 mg kg−1). In conscious SD rats, ZD 7155 and losartan behaved as competitive antagonists and the pressor response curve to angiotensin II was shifted to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response (240 ng kg−1; 10 min infusion). In addition, experiments with conscious rats demonstrated that ZD 7155 could suppress the angiotensin II-induced pressor response for approximately 24 h when ZD 7155 was administered intravenously in a 1.082 μmol kg−1 bolus dose and angiotensin II was given at 240 ng kg−1 (in a 10−min infusion). Experiments in conscious SHRs using ZD 7155 (1.082 μmol kg−1) and losartan (6.495 μmol kg−1) as intravenous boluses indicated that both ZD 7155 and the reference compound losartan exhibited a significant antihypertensive effect. These results demonstrate that ZD 7155 is a potent angiotensin II-type 1 antagonist which is approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response. Furthermore, ZD 7155 may suppress the angiotensin II-induced pressor response for 24 h and in the SHR ZD 7155 induces a pronounced and persistent antihypertensive effect.
Synthesis and Anticonvulsant Activity of Some 1,2,3,3a-Tetrahydropyrrolo[2,1-b]-benzothiazol-, -thiazol-or -oxazol−1−ones in Rodents
Authors: Trapani Giuseppe , Franco Massimo , Latrofa Andrea , Carotti Angelo , Cellamare Saverio , Serra Mariangela , Ghiani Cristina A , Tuligi Graziella , Biggio Giovanni , Liso Gaetano
Published: April 2011

To identify more potent anticonvulsant agents and to gain insights into the structural properties determining the potency of a new class of anticonvulsants, some 3a-substituted tetrahydropyrrolo[2,1-b]benzothiazol-1−ones (1a-d) and the thiazole and oxazole analogues (2a-c and 3a-c, respectively) have been synthesized and tested for anticonvulsant activity against isoniazid-induced seizures in rodents.

The most active compound, 2a, with a median effective dose (ED50, i.p.) of 24.3 mg kg−1 and 15.9 mg kg−1 in mice and in rats, respectively, was more extensively investigated and found to strengthen the effects of diazepam. No clear correlation was observed between the anticonvulsant activity and molecular lipophilicity descriptors of compounds 1−3. Structural similarity between the antiepileptic drug phenobarbital and compounds 1−3 was evidenced by molecular modelling studies and used to derive preliminary structure-activity relationships.

The results demonstrate that 2a is an attractive candidate as an anticonvulsant agent worthy of further study and may help the design of other anticonvulsant drugs.
Possible Cytoprotective Mechanism in Rats of D-002, an Anti-ulcerogenic Product Isolated from Beeswax
Authors: Carbajal Daisy , Molina Vivian , Valdés Suria , Arruzazabala Lourdes , Rodeiro Idania , Más Rosa , Magraner Juan
Published: April 2011

D−002 is an anti-ulcerogenic product, isolated from beeswax, which consists of a well-defined mixture of higher primary aliphatic alcohols. It is highly effective against ethanol-induced ulcers. This study was designed to determine if D-002 shows cytoprotective properties on gastric mucosa in ethanol-induced ulcers. The involvement of endogenous prostaglandins in the protective effect of D−002 was also investigated.

When a subulcerogenic dose of indomethacin (10 mg kg−1) was injected simultaneously with oral administration of ethanol, oral pre-treatment with D-002 (5−100 mg kg−1) partially inhibited the gastric protection. D-002 (5 and 25 mg kg−1) administered to normal rats significantly increased the soluble mucus content and also prevented its reduction in rats with ethanol-induced ulcers. In addition, D-002 administered at 5 and 25 mg kg−1 prevented the increase of vascular permeability induced by ethanol (60%) and reduced the concentration of thromboxane B2 (TXB2) in gastric mucosa of rats with ethanol-induced ulcers.

These results support the hypothesis that the anti-ulcerogenic properties of D-002 could be related to a cytoprotective mechanism.
Studies on the Magnitude and the Mechanism of Cough Potentiation by Angiotensin-Converting Enzyme Inhibitors in Guinea-pigs: Involvement of Bradykinin in the Potentiation
Authors: Takahama Kazuo , Araki Tatsuya , Fuchikami Jun-Ichi , Kohjimoto Yoshiro , Miyata Takeshi
Published: April 2011

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been studied in guinea-pigs.

In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg−1 had no effect on capsaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg−1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg−1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vagal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B2 receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin.

The results indicated that imidapril was less potent than enalapril and captopril in potentiating cough responses induced by capsaicin and citric acid in guinea-pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibitors.
Comparative Study of a Mutant Tissue-type Plasminogen Activator, YM866, with a Tissue-type Plasminogen Activator in a Canine Model of Femoral Arterial Thrombosis
Authors: Kawasaki T , Kaku S , Sakai Y , Takenaka T
Published: April 2011

Because tissue-type plasminogen activator (tPA), used to treat myocardial infarction, has several disadvantages thought to be connected with its low half-life, mutants of tPA have been prepared with longer half-lives. We have compared the thrombolytic effect of such a mutant, YM866, with that of tPA in copper-coil-induced femoral arterial thrombosis in dogs.

One hour after thrombus formation, YM866 was administered by intravenous bolus injection, while tPA was given by the same method or by 60-min infusion under adequate heparinization. Both agents exhibited dose-dependent thrombolysis without systemic fibrinogenolysis. The recanalization rate and recanalization time of YM866 by bolus at 0.2 mg kg−1 were, however, equivalent to those of tPA by infusion at 0.4 mg kg−1 (total dose), whereas the recanalization rate of tPA by bolus was low (0.4 mg kg−1). No significant difference in reocclusion rate, reocclusion time, or patency status after successful thrombolysis was seen.

These results suggest that YM866 administered at a lower dose by intravenous bolus injection exerted a thrombolytic effect equivalent to that of tPA by infusion, and that heparin could not prevent reocclusion after successful thrombolysis even under adequate anticoagulation.
Effect of Amino Acids on the Stability Properties of Nitrofurantoin Suspensions. Flocculation and Redispersion Compared with Interaction Energy Curves
Authors: Gallardo V , Ruiz M A , Vera P , Gonzalez-Caballero F , Delgado A V
Published: April 2011

The influence of the addition of amino acids, lysine, alanine and glutamic acid on the properties of nitrofurantoin suspensions was investigated. Flocculation and redispersability was investigated, taking into account the electrical properties of the nitrofurantoin/solution interface.

We conclude that lysine and glutamic acid, but not alanine, would be suitable amino acids for control of the stability of nitrofurantoin suspensions.
Anti-inflammatory Activity of Polyphosphazene-based Naproxen Slow-release Systems
Authors: Conforti Anita , Bertani Simone , Lussignoli Sabrina , Grigolini Luigi , Terzi Marta , Lora Silvano , Caliceti Paolo , Marsilio Franco , Veronese Francesco M
Published: April 2011

A biocompatible and biodegradable polyphosphazene bearing phenylalanine ethyl ester, imidazole and chlorine (10.7:1:2.5 molar ratio) as substituents of the phosphorus atoms of the polymer backbone was studied for the preparation of polymeric naproxen slow-release systems.

Discs 2.5 cm in diameter and 0.5 mm (thin) or 0.65 mm (thick), loaded, respectively, with 20 and 13.5% naproxen, showed different drug release kinetics, the thin matrices releasing naproxen at a faster rate and for a shorter time. In-vivo studies in rats demonstrated the pharmacological efficacy of these two different delivery systems in the inhibition of acute or chronic inflammatory diseases. Subcutaneous implantation of the thin matrices in rats was found to reduce carrageenan oedema induced both 1 h and 7 days after implantation. Rats implanted with thick matrices showed a reduction in chronic inflammation caused by adjuvant arthritis. Approximately 78% inhibition of arthritic oedema was found 28 days after subcutaneous administration of the matrices whereas 28.7% inhibition was found after daily oral administration of naproxen. Blood levels of naproxen in arthritic rats after matrix implantation showed the presence of drug up to day 28.

These positive results have encouraged us to study a controlled-release system suitable for use in man.
High-performance Thin-layer Chromatography for the Determination of Cetirizine in Human Plasma and Its Use in Pharmacokinetic Studies
Authors: Pandya K K , Bangaru R A , Gandhi T P , Modi I A , Modi R I , Chakravarthy B K
Published: April 2011

A rapid and sensitive high-performance thin-layer chromatography (HPTLC) assay has been developed for the measurement of cetirizine in human plasma and its utility for pharmacokinetic study has been evaluated.

In the proposed HPTLC method, protein-bound cetirizine was freed by proteolysis of plasma proteins by incubating the plasma with 0.35% pepsin and then extracting with 2 mL pH 5.0 phosphate buffer, followed by 4 mL chilled chloroform. The chloroform layer was separated and concentrated. An aliquot of the extract was then spotted on precoated silica-gel 60 F254 plates using a Camag Linomat IV autosampler. Quantification was with the help of a dual-wavelength TLC scanner. The proposed method had a recovery of 98% and the lowest amount of cetirizine that could be detected was 50 ng.

The method was applied for the determination of the plasma levels and pharmacokinetic parameters of cetirizine after oral administration of two marketed preparations in healthy volunteers and the pharmacokinetic parameters determined by the proposed method were in agreement with previously reported values.
Saturable Function of P-Glycoprotein as a Drug-efflux Pump in Multidrug-resistant Tumour Cells
Authors: Miyamoto Ken-Ichi , Koga-Takeda Keiko , Koga Kenjiro , Ohshima Taeyuki , Nomura Masaaki
Published: April 2011

P-glycoprotein acts as an active drug-efflux pump in multidrug-resistant tumour cells. We studied the capacity of P-glycoprotein to extrude drugs from the cells.

For nanomolar concentrations of vinblastine P388/ADR cells, which overexpress P-glycoprotein in the plasma membrane, accumulated vinblastine, at 37°C for 30 min, to a much lower extent than the sensitive cells (P388/S), while in the micromolar range the cellular concentration was similar for both types of cells. When cells were incubated with a low (10 nM) or high concentration (1 μM) of vinblastine while energy deprived, the vinblastine concentration increased only in the resistant cells incubated with the low concentration of vinblastine, and this increased level was lowered to the level under the normal conditions by addition of glucose. In contrast, the cellular concentrations in other cases were increased to the normal level by glucose. After cells were loaded with the low concentration of vinblastine, the cellular vinblastine was extruded more rapidly from the resistant cells than from the sensitive cells. The courses of vinblastine efflux from the cells loaded with the high concentration of vinblastine were similar in both types of cells. NA-382, a reported P-glycoprotein inhibitor, effectively increased the intracellular vinblastine and inhibited the drug efflux only from multidrug-resistant cells, P388/ADR and AH66 cells, which were incubated with the low concentration of vinblastine. Cellular uptake of NA-382 was also less in P388/ADR cells than in P388/S cells in culture with 10 nM but not 1 μM of the agent, and this low level was reversed to the level in the sensitive cells by 10 μM vinblastine.

These results indicate that P-glycoprotein as a drug-efflux pump works effectively under low extracellular concentrations of substrates, but does not under the high concentrations.
Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney
Authors: Masereeuw Rosalinde , Moons Miek M , Russel Frans G M
Published: April 2011

The effect of protein binding on kidney function has been studied by investigating the renal accumulation and secretion of the hippurate analogue 2-methylbenzoylglycine in the isolated perfused rat kidney in the absence and presence of bovine serum albumin (BSA).

Experiments were performed with either 2.5% pluronic or a combination of 2.2% pluronic and 2% BSA as oncotic agents; a wide concentration range (1–190 μg mL−1) of 2-methylbenzoylglycine was studied. Tubular secretion appeared to be a function of the amount of unbound drug in the perfusate and was best described by a model consisting of a high and low affinity Michaelis-Menten term. Parameters obtained after the analysis of renal excretion data were maximum transport velocity for the high affinity site (TM,H) = 3.0 ± 2.8 μg min−1, Michaelis-Menten constant for tubular transport for the high affinity site (KT,H) = 0.5 ± 0.8 μg mL−1, maximum transport velocity for the low affinity site (TM,L) = 250 ± 36 μg min−1, and Michaelis-Menten constant for tubular transport for the low affinity site (KT,L) = 62 ± 17 μg mL−1. The compound accumulated extensively in kidney tissue, ratios up to 175 times the perfusate concentration were reached. Accumulation data were best analysed by a two-site model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity of the high affinity site (RM,H) = 26 ± 23 μg g−1, affinity constant for renal accumulation at the high affinity site (KA,H) = 0.2 ± 0.4 μg mL−1, theoretical maximum capacity of the low affinity site (RM,L)= 1640 ± 1100 μg g−1 and affinity constant for renal accumulation at the low affinity site (KA,L) = 60 ± 58 μg mL−1.

The very high accumulation in kidney tissue could be explained by active tubular uptake, mediated by the secretory mechanisms involved, and dependent on the amount of free drug in the perfusate. This study shows that anionic drugs, subject to active secretion, may reach high concentrations in tubular cells even at low plasma concentrations.
In-vitro and Ex-vivo Inhibition of Blood Platelet Aggregation by Naftazone
Authors: Durand P , Bloy C , Peltier-Pujol F , Blache D
Published: April 2011

Because of the considerable interest in the role of platelets and antiplatelet therapy in cardiovascular disease, including the aggregation of platelets to each other during arterial thrombosis and atherogenesis, we have studied the effect of naftazone (Etioven), an original vasculotropic drug on platelet aggregation.

Rat and human platelets were prepared and incubated in-vitro with different concentrations of naftazone. We found that naftazone inhibited both platelet secretion and aggregation in platelet-rich plasma (PRP) and washed platelets after stimulation with thrombin or ADP. Rats were also treated intraperitoneally for five days with various naftazone doses (0.125-10 mg kg−1) and ex-vivo platelet aggregation compared, at various times after the last injection, with that of control animals. Inhibition by naftazone was dose-dependent in both PRP and isolated platelets. The inhibition was transient, a maximum value (∼ 50%) being obtained about 3–6 h after the last injection, with a return to near-control values after 24 h. Naftazone also facilitated platelet deaggregation after in-vitro stimulation with thrombin or ADP. In another series of experiments, rats were treated intraperitoneally for five days with 10 mg kg−1 of aspirin, ticlopidine, dipyridamole or naftazone. Platelets were prepared and tested for aggregation 90 min after the last injection. Thrombin-induced aggregation in PRP and washed platelets was significantly reduced after in-vivo treatment with ticlopidine and naftazone. Except for dipyridamole, all the drugs inhibited ex-vivo ADP-induced aggregation in PRP. In isolated platelet preparation, only naftazone induced a significant inhibition of ADP-or thrombin-stimulated aggregation.

We conclude that naftazone inhibits platelet aggregation in-vitro and ex-vivo.