bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiarrhythmic and Electrophysiological Effects In-vivo of the Major Metabolite of Org 7797 Found in Canine and Rodent Liver Homogenate Preparations
Authors: Winslow E , Campbell J K , Delbressine L
Published: April 2011

Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo.

Org 20781 (0·5–2·0 mg kg−1 i.v.) inhibited the development of early ischaemia-induced arrhythmias in rats, suppressed spontaneous ventricular tachycardia (VT) in conscious dogs with 24-h old infarcts, and prevented electrical induction of VT in dogs with 5–6-day old infarcts, actions associated with slowing of conduction at all levels of the myocardium. Cardiac refractory periods were only modestly prolonged whilst repolarization was unchanged. Peak plasma levels of the parent compound (infused to total doses of 2–4mg kg−1) associated with suppression of late arrhythmias were 6–18 μm, whilst the mean plasma elimination half-life (in normal dogs) was 107 min.

It was concluded that the major metabolite has a similar antiarrhythmic and electrophysiological profile to the parent compound, is at least half as potent and may contribute to the therapeutic effects of Org 7797 administration.
Effects of Ginsenosides on Vasodilator Nerve Actions in the Rat Perfused Mesentery are Mediated by Nitric Oxide
Authors: Peng Chang-Fu , Li Yu-Jie , Li Yuan-Jian , Deng Han-Wu
Published: April 2011

This study was designed to explore the effect of ginsenosides, saponins from Panax ginseng, on the vasodilator nerve actions in the rat perfused mesentery and the mechanism of this effect.

In the rat perfused mesentery, when adrenergic nerves were blocked by guanethidine (5 × 10−6 M) and vascular muscle tone was increased with methoxamine (5 × 10−6-10−5 M), transmural field stimulation produced a frequency-dependent vasodilator response, which is due to the release of calcitonin generelated peptide; ginsenosides significantly suppressed this vasodilator response in a concentration-dependent manner (3–30 μg mL−1). After pretreatment with saponin (50 μg mL−1, 3min) to damage endothelial cells, this suppressing effect of ginsenosides was unaltered. However, the effect was abolished by Nω-nitro-l-arginine methyl ester (L-NAME) (10−4 M), an inhibitor of nitric oxide synthesis and addition of l-arginine (3 × 10−4 M) restored this suppressing effect. Methylene blue (10−5 M), an inhibitor of guanylate cyclase, also abolished the suppressing effect of ginsenosides. However, ginsenosides did not alter the relaxation responses caused by exogenous calcitonin gene-related peptide administration.

We conclude that ginsenosides can produce an inhibitory effect on the vasodilator response prejunctionally in the rat perfused mesentery and that this effect of ginsenosides may be mediated by nitric oxide released from non-adrenergic, non-cholinergic nerves.
Chemical and Pharmacological Studies of Phyllanthus caroliniensis in Mice
Authors: Filho Valdir Cechinel , Santos Adair R S , De Campos Rafael O P , Miguel Obdulio G , Yunes Rosendo A , Ferrari Franco , Messana Irene , Calixto João B
Published: April 2011

The aim of this study was to isolate and characterize the constituents of the hydroalcoholic extract (HE) of the leaves, stems and roots from P. caroliniensis, and also to evaluate the preliminary antinociceptive action of the HE and purified compounds in mice.

Phytosterols, quercetin, gallic acid ethyl ester and geraniin were identified in P. caroliniensis on the basis of 1H and 13C NMR spectral data and by mixed co-TLC and co-HPLC injection with authentic samples. The HE of P. caroliniensis (10-100 mg kg−1, i.p.) inhibited, in a dose-related manner, acetic acid-induced abdominal constrictions in mice, with a mean ID50 value of 23.7 mg kg−1. In the formalin test, the HE given intraperitoneally (1-30 mg kg−1) or orally (25-600 mg kg−1) caused graded inhibitions of both the neurogenic (first phase) and the inflammatory response (late phase) of formalin-induced licking. The HE was 54-fold more effective in inhibiting the late phase than it was in inhibiting the first phase of the formalin test, with mean ID50 values of 3.6 and 196.4 mg kg−1, respectively. The HE failed, however, to affect the oedematogenic response associated with the late phase of formalin-induced pain. In addition, the reference drug, aspirin, given intraperitoneally (1-100 mg kg−1) or orally (100-600 mg kg−1), caused significant inhibition of the late but not the first phase of the formalin test. Pharmacological analysis also revealed that quercetin, gallic acid ethyl ester and a semi-purified fraction of flavonoids (1-100 mg kg−1, i.p.) exhibited graded and significant antinociception against acetic acid-induced abdominal constriction. The mean ID50 values (mg kg−1) for these effects were: 18.8, 34.7 and 5.3, respectively.

It is concluded that quercetin, gallic acid ethyl ester and some as yet unidentified flavonoids might account for the antinociceptive action reported for the HE of P. caroliniensis.
Influence of the Carrier on the Intrinsic Rate of Dissolution of Diazepam in Interactive Mixtures
Authors: Supabphol Roongtawan , Stewart Peter J
Published: April 2011

The use of interactive mixtures of drugs adhering to the surface of carriers can promote drug dissolution. The mechanism of dissolution of such mixtures has been studied using the rotating-disc method under conditions eliminating secondary influences such as carrier surface characteristics and drug particle aggregation. Levich plots were used to characterize the dissolution behaviour.

Diazepam-compactrol interactive mixtures had initial dissolution rates similar to that of pure diazepam owing to the deposition of a continuous layer of diazepam on the disc surface from the interactive mixture. Linear Levich plots were produced at all drug loadings and the presence of compactrol in the disc slightly enhanced dissolution rates. Dissolution rates for diazepam-emcompress interactive mixtures were lower than those of pure diazepam. The Levich plots for these systems were non-linear with increasing negative curvature as the diazepam loading decreased. The rate of dissolution of diazepam in the lactose interactive mixture was markedly higher than that of pure diazepam, but high diazepam loadings in the lactose mixtures inhibited diazepam dissolution. Rapid carrier dissolution caused surface retraction of the disc, enhancing the dissolution rate. The Levich plots showed an upward curvature due to turbulence.

Linear Levich plots for diazepam and other benzodiazepines and for diazepam-compactrol interactive mixtures showed that their dissolution in pH 5 phosphate buffer was diffusion-controlled. The Levich plots for diazepam-emcompress interactive mixtures were indicative of some interfacial control during dissolution, but the hypothesis of common ion precipitation of dissolved carrier, calcium phosphate, onto the disc surface did not fully explain this effect.
A Pharmacokinetic Study of Sublingual Aerosolized Morphine in Healthy Volunteers
Authors: Watson Neil W , Taylor Kevin M G , Joel Simon P , Slevin Maurice L , Eden Osborn B
Published: April 2011

A pharmacokinetic study was undertaken to compare the pharmacokinetics of morphine after an intravenous dose with the pharmacokinetics after a sublingual dose administered from an aerosol.

Plasma levels of morphine, morphine-3-glucuronide and morphine-6-glucuronide were measured in five normal volunteers after morphine administration by the intravenous route and from a novel sublingual pressurized aerosol formulation. The mean (± s.d.) bioavailability of the sublingual aerosol morphine was 19.7 ± 6.7%. The morphine-3-glucuronide/morphine and the morphine-6-glucuronide/morphine ratios were 5.1 ± 1.6 and 1.2 ± 0.4, respectively, for the intravenous route and 28.3 ± 11.3 and 5.2 ± 1.4, respectively, for the sublingual route. The combined total areas under the plots of systemic concentration against time (AUC) for the metabolites after the two routes was not significantly different.

When compared with published data for oral administration the results demonstrate that the sublingual aerosol morphine might provide an alternative to conventional methods of morphine delivery, and has similar pharmacokinetics to a sublingual morphine tablet. It has no particular pharmacokinetic advantages over oral morphine, except a potential for a faster onset of analgesia. Bioavailability, maximum plasma concentration, Cpmax, and the time at which the maximum plasma concentration is reached, Tmax, are equivalent to those for orally administered morphine.
Pharmacokinetic Analysis of the Absorption Characteristics of Diclofenac Sodium in Man by use of a Multi-segment Absorption Model
Authors: Mahmood Iftekhar
Published: April 2011

The pharmacokinetic analysis of an oral sustained-release preparation of diclofenac sodium has been investigated using multi-segment absorption models in which it has been assumed that the gastrointestinal tract can be divided into several segments in each of which the drug has its own lag-time and absorption rate constants.

Plasma concentration-time data for sustained release diclofenac sodium in man were fitted both by a conventional pharmacokinetic method assuming first-order absorption and by a multi-segment absorption model. The plasma concentration of diclofenac sodium calculated on the basis of the multi-segment absorption model was found to correlate with the observed plasma concentration.

It was concluded that diclofenac sodium data can be better described by a multi-segment absorption model than by a conventional pharmacokinetic model. The results also show that multi-segment absorption models are suitable for pharmacokinetic analysis of plasma drug-concentration data with irregular or multiple peaks in the absorption profiles, and also for the pharmacokinetic analysis of sustained-release preparations.
Bioavailability and In-vitro/in-vivo Correlation for Propranolol Hydrochloride Extended-release Bead Products Prepared Using Aqueous Polymeric Dispersions
Authors: Rekhi Gurvinder Singh , Jambhekar Sunil S
Published: April 2011

The influence of formulation and extrinsic factors has been investigated for the in-vitro release of propranolol hydrochloride from controlled-release beads prepared using aqueous polymeric dispersions, Aquacoat and Surelease. A single-dose three-way crossover bioavailability study of two extended-release experimental formulations (80 mg), Inderal LA (80 mg) and an Inderal immediate-release dosage form (2 × 40 mg) was also conducted and a comparative analysis of pharmacokinetic parameters and the in-vitro release profiles was performed to assess in-vitro/in-vivo correlation.

Analysis showed that the in-vitro release data appeared to follow zero-order release kinetics. Intensity of agitation and dissolution method were found to have no significant effect on drug release from beads prepared using either of the coating dispersions studied or Inderal LA. Release of drug from beads coated with Aquacoat was faster in basic media than in acidic media; Surelease-coated beads, however, showed release characteristics that were less sensitive to changes in the pH of the dissolution fluid, and Inderal LA beads showed slower release profiles in acidic medium than in other dissolution media studied. Pharmacokinetic analysis of the data revealed sustained-release absorption characteristics without any evidence of dose-dumping from any of the extended-release dosage forms studied. Regression analysis of the fraction of drug absorbed against the percentage of the drug released in-vitro, at the corresponding times, yielded good in-vitro/in-vivo correlation (level A) for all the extended-release formulations studied.

The results showed that there was no dose-dumping from any of extended-release formulations and that the relative bioavailabilities of the experimental formulations were superior to that of the marketed formulation.
Effectiveness and Toxicity Screening of Various Absorption Enhancers in the Rat Small Intestine: Effects of Absorption Enhancers on the Intestinal Absorption of Phenol Red and the Release of Protein and Phospholipids from the Intestinal Membrane
Authors: Yamamoto Akira , Uchiyama Tomomi , Nishikawa Reiko , Fujita Takuya , Muranishi Shozo
Published: April 2011

Sodium glycocholate, sodium taurocholate, sodium deoxycholate, EDTA, sodium salicylate, sodium caprate, diethyl maleate, N-lauryl-β-D-maltopyranoside, linoleic acid polyoxyethylated (60 mol) mixed micelles (all 20 mM) have been ranked in order of their effectiveness as enhancers of the absorption of drugs in the rat small intestine, by use of an in-situ loop model with phenol red as a model drug. Local toxicity in rats was examined by assessing protein and phospholipid release as biological markers.

Of the absorption enhancers, sodium deoxycholate, EDTA and N-lauryl-β-D-maltopyranoside were the most effective; sodium deoxycholate and EDTA, however, caused significant release of protein and phospholipids. N-lauryl-β-D-maltopyranoside, on the other hand, did not damage the small intestinal membrane. Sodium taurocholate enhanced phenol red absorption from the small intestine and resulted in little or no protein and phospholipids release. Sodium salicylate, diethyl maleate and the mixed micelles had no absorption-promoting effects on phenol red. There was good correlation between the area under the plasma concentration-time curve for phenol red and the amounts of protein and phospholipid released in the presence of absorption enhancers.

From these results it might be concluded that N-lauryl-β-D-maltopyranoside and sodium taurocholate are effective absorption enhancers which have low toxicity levels at a concentration of 20 mM.
Characterization of α-Adrenoceptor Activity in Term-newborn Piglet Mesentery
Authors: Ferrara J J , Hoang T V , Choe E U , Lippton H L , Hyman A L , Flint L M
Published: April 2011

For further characterization of neonatal mesenteric α1-adrenoceptor populations, an extracorporeal perfusion circuit was established to control intestinal blood flow in 0-2 day old piglets.

Activation of α1-adrenoceptors was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intra-mesenteric arterial injection of methoxamine and noradrenaline. Peripheral intravenous injections of WB 4101 (a competitive α1A-adrenoceptor antagonist), but not clorethylclonidine (CEC, an α1B-adrenoceptor antagonist), significantly (P < 0.05, analysis of variance) blunted mesenteric vasoconstrictor responses to those agonists.

That the mesenteric vasoconstrictor response to mesenteric plexus stimulation was unaltered by CEC, but was muted by both WB 4101 and SK&F 104856 (a post-junctional α1- and α2-adrenoceptor antagonist) suggests that pre- and post-junctional α1A-adrenoceptors are present and functional at birth.
The Failure of Substrate pKa to Influence the Microsomal Formation of Amides from N-Benzylamines: the Microsomal Metabolism of N-Benzyl Pyrrolidine, N-Benzyl Carbazole and N-Acetyl-N-benzyl-4-methylaniline
Authors: Ulgen Mert , Gorrod John W
Published: April 2011

The in-vitro hepatic microsomal metabolism of N-benzylpyrrolidine (NBP), N-benzylcarbazole (NBC) and N-acetyl-N-benzyl-4-methylaniline (NANBMA) has been studied, using hamster microsomal preparations, to establish whether the corresponding amide is formed.

Amide formation was not observed with any of the substrates utilized, although several metabolic products were detected by HPLC with UV detection. These included the oxidative debenzylation products (for all substrates), ring hydroxylated products (for NBC) and a lactam metabolite (for NBP).

The results support the concept that the metabolic conversion of benzylic amines to the corresponding amide involves an N-oxidative step.
Age-dependent Alteration of the Serum-unbound Fraction of Nicardipine, a Calcium-channel Blocker, in Man
Authors: Sugioka Nobuyuki , Koyama Hikaru , Kawakubo Mariko , Ohta Toshio , Kishimoto Hideki , Mori Satoru , Nakajima Kenji
Published: April 2011

To determine whether the age-dependent increase in the pharmacological effect of calcium-channel blockers is a result of age-dependent alteration of the unbound fraction the drug in serum, the unbound fraction of the nicardipine was investigated in the serum of 38 adults.

The unbound concentration of nicardipine in serum to which nicardipine (205.4 ng mL−1) had been added was determined by ultracentrifugation to range from 0.49 to 4.01% (mean±s.d., 1.55 ± 0.78%). Non-glycosylated albumin was most strongly correlated with age (r = 0.901). Total bilirubin was weakly correlated with age whereas levels of α-1-acid glycoprotein, triglycerides and glycosylated albumin were not correlated with age. A significant (P < 0.01) linear correlation was obtained between the unbound fraction of nicardipine and parameters such as age, albumin, albumin/globulin ratio, albumin/glycosylated albumin ratio, non-glycosylated albumin and total bilirubin. To assess the relative effect of each variable on the unbound fraction of nicardipine, stepwise multiple linear regression was performed using age and biochemical parameters. The three variables (non-glycosylated albumin, total bilirubin and age) were entered into the regression equation.

The results of this study showed that the major ligand of nicardipine in serum was non-glycosylated albumin, which decreased with age. It was, moreover, shown that the serum-unbound concentration of nicardipine increased with age. This finding would be one factor accounting for the increase in the pharmacological effect of nicardipine with age. In addition, our predicted model for the unbound fraction of nicardipine might be useful in determining the appropriate nicardipine dose for the elderly.
Chemical Stability of Artesunate Injection and Proposal for its Administration by Intravenous Infusion
Authors: Batty Kevin T , Ilett Kenneth F , Davis M E , Timothy
Published: April 2011

Artesunate, the only artemisinin analogue that can be given intravenously, produces rapid parasite and fever clearance in falciparum malaria. A significant therapeutic problem is a high, late recrudescence rate, probably due to short half-lives of both artesunate and its active metabolite dihydroartemisinin relative to conventional dosing intervals. One method of extending the duration of action of artesunate could be to administer the drug by infusion rather than bolus injection, provided that it is chemically stable at ambient temperature.

Artesunate was found to be stable in 0ṁ9% w/v sodium chloride at 9°C, 23°C and 36ṁ5°C for 130, 10ṁ6 and 1ṁ6 h, respectively. Interpolating from an Arrhenius plot, artesunate should be stable for approximately 4 h at 30°C, a temperature representative of ambient conditions in tropical countries. Exposure to light did not affect the degradation rate. Single compartment pharmacokinetic modelling was used to evaluate potential differences in artesunate and dihydroartemisinin plasma concentrations following administration of artesunate by intravenous bolus or infusion. A bolus injection of artesunate at a dose of 4 mg kg−1 gives a peak concentration of 5ṁ3 mg L−1, falling to 0ṁ005 mg L−1 at 5 h. The same dose infused over 4h results in a peak concentration of 0ṁ92 mg L−1 falling to 0ṁ005 mg L−1 at 8h. Simultaneous modelling of dihydroartemisinin showed that while its peak plasma concentration was reduced by 27% and the peak delayed by 2.5 h following artesunate administration by infusion, substantially higher concentrations were maintained compared with those predicted after bolus artesunate.

These data indicate that artesunate can be administered as a high-dose intravenous infusion, thus avoiding high plasma concentrations. This strategy also has the potential to prolong the duration of antimalarial effect and reduce toxicity, and consequently improve clinical outcome in seriously ill patients.
In-vitro Evaluation of Biphenylyl Acetic Acid-β-Cyclodextrin Conjugates as Colon-targeting Prodrugs: Drug Release Behaviour in Rat Biological Media
Authors: Hirayama Fumitoshi , Minami Kunihiro , Uekama Kaneto
Published: April 2011

Biphenylyl acetic acid was selectively conjugated to one of the primary hydroxyl groups of β-cyclodextrin through an ester- or amide-linkage, and the physicochemical properties (aqueous solubility and hydrolysis) were investigated.

Aqueous solubility of the conjugates was lower than those of either drug or parent β-cyclodextrin. The amide conjugate was stable in aqueous solution and in rat biological fluids and gastrointestinal contents. The ester conjugate was hydrolysed to β-cyclodextrin and biphenylyl acetic acid at moderate rates resulting in a V-shaped rate-pH profile in aqueous solution. The ester conjugate released the drug preferentially when incubated with the contents of caecum or colon, whereas no appreciable drug release was observed on incubation with contents of stomach or intestine, nor on incubation with intestinal or liver homogenates, nor on incubation with rat blood.

The present results suggest that the ester-type drug conjugate of β-cyclodextrin may serve as a colon-targeting prodrug.
Effects of 5−Lipoxygenase Inhibitors on Interleukin Production by Human Synovial Tissues in Organ Culture: Comparison with Interleukin−1−synthesis Inhibitors
Authors: Rainsford K D , Ying C , Smith F
Published: April 2011

Prostaglandins and leukotrienes differentially regulate the production of interleukin−1 (IL−1) in monocytes. It was, therefore, decided to investigate the effects of some 5−lipoxygenase inhibitors compared with standard IL−1−synthesis inhibitors on the production of IL−1 by human synovial tissue explants in organ culture. Human synovial (from hip/knee arthroplasty) or porcine tibio-tarsal joint synovial explants were incubated in organ culture in Dulbecco's Modified Eagle's Medium + 5% foetal calf serum in the presence of the test compounds or solvents (controls), or media alone for 1−5 days. Total bioactive IL−1 was assayed in the medium (following serial dilution or with polyethylene glycol 8000 added in some assays to remove inhibitors) using the D−10 T-cell bioassay. Some assays of interleukins 1α, 1β, 6 or 8 were performed by ELISA. Of the 5−lipoxygenase inhibitors investigated, MK-886 (3−(1−(4−chlorobenzyl)−3-tert-butyl-thio−5−isopropylindol−2−yl)−2,2−dimethyl propanoic acid), L−656,224 ((7−chloro−2−[4−methoxypenyl]methyl)−3−methyl−5−propyl−4−benzofuranol), PF−5901 and tepoxalin were the most potent inhibitors of IL−1 production. While the PF−5901 was effective at 5–30 μM and tepoxalin was effective at 1−10 μM, the others were the most potent having minimal inhibitory activity in the range of 0.01−0.1 μM. The presumed IL−1−synthesis inhibitors, tenidap and IX−207,887, were inactive at concentrations of 30−50 μM. Leukotriene B4 (1−100 ng mL−1) added to MK−886 (5 μM)-treated cultures reversed the inhibitory effects of the latter on IL−1, confirming the role of 5−lipoxygenase products in the regulation of IL−1 production. Addition of polyethylene glycol 8000 to MK−886−treated cultures eliminated the inhibitory effects of this drug, suggesting that this drug exerts its effects by promoting production of IL−1 inhibitors. MK−886 also inhibited synovial production of two other pleiotrophic cytokines which it regulates, IL−6 and IL−8. The results suggest that some 5−lipoxygenase inhibitors may be usefully employed in regulating production of those interleukins involved in joint cartilage destruction.
Pyridine Derivatives Stimulate Phosphatidylcholine Secretion in Primary Cultures of Rat Type II Pneumocytes
Authors: Kai Hirofumi , Murahara Koichiro , Isohama Yoichiro , Takahama Kazuo , Oda Yoshiaki , Hamamura Ichiro , Yoshitake Kazuhisa , Miyata Takeshi
Published: April 2011

We have examined the effects of pyridine derivatives on phosphatidylcholine secretion in primary cultures of rat type II pneumocytes.

Of 12 pyridine derivatives, 4−aminopyridine, 4−dimethylaminopyridine and 4−pyrolidinopyridine had a stimulatory effect on phosphatidylcholine secretion, whereas other derivatives had little effect. The stimulatory effect of 4−aminopyridine was concentration- and time-dependent, and was inhibited by the acetoxymethyl ester of 1,2−bis(2−aminophenoxy)ethane-N, N, N', N'-tetraacetic acid (3 μM), an intracellular Ca2+ chelator. In addition, the stimulatory effect of 4−aminopyridine was suppressed by W−7 (N-(6−aminohexyl)−5−chloro−1−napthalene-sulphonamide) (10 μM), a calmodulin inhibitor, and sphingosine (10 μM) and staurosporine (01μM), protein kinase C inhibitors.

These results indicate that several pyridine derivatives stimulate phosphatidylcholine secretion in type II pneumocytes.
Susceptibility of Mice to Bacterial and Fungal Infections after Intragastric Administration of Ebselen
Authors: Nozawa R , Arai M , Kuruto R , Motohashi T , Masayasu H
Published: April 2011

The seleno-organic compound ebselen (2−phenyl−1,2−benzisoselenazol−3(2H)-one) has anti-inflammatory activity and exhibits glutathione peroxidase-like activity in-vitro. Ebselen inhibited candidacidal activity over the same range of concentrations as it inhibited the production of microbicidal H2O2 by human neutrophils and macrophage-like cells. Therefore, the long-term administration of ebselen might be expected to induce an immunocompromised state in the host. To examine such a possibility, mice (5−weeks-old ddY, male) were given daily intragastric doses of 0, 10 or 100 mg kg−1 ebselen for 21 days and then infected intraperitoneally with Candida albicans (108 cells/mouse), Pseudomonas aeruginosa (1.5 times 107 cells/mouse) or methicillin-resistant Staphylococcus aureus (5 times 108 cells/mouse). Ebselen at none of the tested doses affected the increase in body weight of mice during administration of the drug. No evidence was obtained that mice became more susceptible to the various microorganisms after the administration of ebselen at any tested dose.
Serum Corticosterone Increases Reflect Enhanced Uptake Inhibitor-induced Elevation of Extracellular 5−Hydroxytryptamine in Rat Hypothalamus
Authors: Fuller Ray W , Perry Kenneth W , Hemrick-Luecke Susan K , Engleman Eric
Published: April 2011

The increase in extracellular 5−hydroxytryptamine (5−HT) in rat hypothalamus following administration of fluoxetine, a 5−HT-uptake inhibitor, was enhanced by the injection of LY206130 (1−[1−H-indol−4−yloxy]−3−[cyclohexylamino]−2−propanol maleate), a 5HT1A receptor antagonist, or by L−5−hydroxytryptophan (L−5−HTP), the 5−HT precursor. Elevation of serum corticosterone, measured as a functional output of hypothalamic 5−HT pathways, was greater in rats treated with fluoxetine plus LY206130 or with fluoxetine plus L−5−HTP than in rats treated with the agents alone.

Synergism between effects of fluoxetine and L−5HTP has often been reported, but this is the first report of an increased functional effect when a 5−HT1A receptor antagonist is combined with a 5−HT uptake inhibitor to augment the increase in extracellular 5−HT.
Acetylcholinesterase Inhibition and Protection by Dizocilpine (MK−801) Enantiomers
Authors: Galli Alessandro , Mori Francesca
Published: April 2011

The optical isomers of the N-methyl-d-aspartate (NMDA) receptor ion-channel blocker dizocilpine (MK−801) were shown to interact with electric eel and rat brain acetylcholinesterase (AChE) in a mixed competitive-noncompetitive way. The (-) form, pharmacologically less active, was the most potent of the two isomers as an AChE inhibitor (K1 for electric eel and rat brain AChE being 6ṁ2 and 17ṁ9μM, respectively, compared with 200 and 450 μM, respectively, of the (+) form). Both enantiomers premixed with AChE preparations, dose-dependently protected the enzyme from inactivation by diisopropylfluorophosphate (DFP). The maximal protective effects against 40 and 10 μM DFP were in the ranges 10ṁ7−23ṁ8 and 19ṁ5−31ṁ4% of control enzymic activity for the (+) and (-) forms of dizocilpine, respectively. The extent of the protective effect against DFP was increased up to 80ṁ1% of control enzymic activity for (-)-dizocilpine and to 38ṁ4% for (+)-dizocilpine by diluting the enzymic mixtures 1000 times after treatment with the organophosphate agent. The two enantiomers added to AChE 15 min after DFP, failed to reactivate the enzyme. Finally, it was shown that (+)- and (-)-dizocilpine dose-dependently and competitively decreased the DFP bimolecular reaction constant, Ki. We conclude that dizocilpine exerts a protective action towards AChE against irreversible DFP inhibition, but the molecular mechanism of such an action is at present unclear.
α-Trinositol: A Functional (Non-receptor) Neuropeptide Y Antagonist in Vasculature
Authors: Sun Xiangying , You Junping , Hedner Thomas , Erlinge David , Fellström Bengt , Yoo Heahyun , Wahlestedt Claes , Edvinsson Lars
Published: April 2011

Neuropeptide Y is a sympathetic co-neurotransmitter released with noradrenaline upon sympathetic nerve stimulation. This study describes the ability of a synthetic inositol phosphate, α-trinositol (d-myo-inositol 1,2,6−triphosphate; PP 56) to antagonize vasoconstrictor responses to neuropeptide Y in-vitro as well as in-vivo.

In human and guinea-pig isolated arteries α-trinositol potently (10 nM to 1 μM extracellular concentration) suppressed the constriction evoked by neuropeptide Y alone, the potentiation by neuropeptide Y of noradrenaline-evoked constriction, and the neuropeptide Y-induced inhibition of relaxation. Moreover, in the pithed (areflexive) rat, a non-adrenergic portion of the pressor response to preganglionic sympathetic nerve stimulation was sensitive to α-trinositol. As studied in the recently cloned human (vascular-type) Y1 receptor, the action of α-trinositol does not occur through antagonism at the neuropeptide Y recognition site nor does it induce allosteric changes of this receptor. However, we found α-trinositol to inhibit the rise in intracellular Ca2+ as well as inositol triphosphate concentrations induced by neuropeptide Y.

It is, therefore, proposed that α-trinositol represents a non-receptor, but yet selective antagonist of neuropeptide Y in vasculature, opening up the possibility to investigate involvement of neuropeptide Y in sympathetic blood pressure control and in cardiovascular disorders.
3−Nitropropionic Acid Exacerbates [3H]GABA Release Evoked by Glucose Deprivation in Rat Striatal Slices
Authors: Boireau A , Meunier M , Doble A
Published: April 2011

3−Nitropropionic acid (3−NPA) is a metabolic poison that produces lesions of striatal intrinsic neurones such as γ-aminobutyric acid (GABA) neurones. This study was carried out to determine whether 3−NPA would impair the ability of striatal GABAergic neurones to withstand hypoglycaemic stress.

3−NPA (500 μM) did not affect [3H]GABA release from striatal slices under normal (11 mM) glucose concentrations. When the glucose concentration was lowered to 0ṁ3 mM, however, 3−NPA greatly potentiated the leakage of [3H]GABA from the slices. Blockade of N-methyl-d-aspartate (NMDA) or α-amino−3−hydroxy−5−methyl−4−isoxazolepropionic acid (AMPA) receptors with 1 μM 5−methyl−10,11−dihydro−5H-dibenzo[a,d]cyclohepten−5,10−imine (MK−801) or 10 μM 2,3−dihydroxy−6−nitro−7−sulpha-moylbenzo[F]quinoxaline (NBQX), respectively, or a combination of both, had no effect. However, blockade of voltage-dependent sodium channels with tetrodotoxin totally antagonized the [3H]GABA overflow induced by the combination of 3−NPA and hypoglycaemia. Riluzole (10 to 100 μM), a neuroprotective agent that stabilizes the inactivated state of the voltage-dependent sodium channel, also dose-dependently antagonized the increase in [3H]GABA release induced by the combination of the two stresses.
Effects of Endothelin B Antagonist RES−701−1 on Endothelin-induced Contractile Responses In-vivo and In-vitro in Guinea-pigs
Authors: Ikemura Toshihide , Ohmori Kenji , Tanaka Takeo , Matsuda Yuzuru , Kitamura Shigeto
Published: April 2011

The effects of an endothelin (ET)-receptor B-specific antagonist, RES−701−1, on ET-induced contraction of guinea-pig trachea and on ET-induced bronchoconstriction in anaesthetized guinea-pigs were investigated.

In the epithelium-removed tracheal preparation, 1 times 10−5 M RES−701−1 inhibited contractions induced by the ETB-specific agonist sarafotoxin S6c (pKB = 6ṁ10). In the epithelium-intact tracheal preparation, RES−701−1 (1 times 10−5 M) inhibited the ET−3−induced contraction (pKB = 5ṁ27), but enhanced the ET−1−induced contraction significantly and shifted the concentration-response curve to the left. The maximal responses of ET−1- and ET−3−induced contraction were augmented by epithelium removal by 1ṁ5 and 1ṁ8−fold, respectively. Against ET−3−induced contraction in the tracheal preparation without epithelium, RES−701−1 (0ṁ3−10 times 10−6 M) antagonized the contraction in a concentration-dependent manner (pA2 = 5ṁ9). On the other hand, RES−701−1 (1 times 10−5 M) did not affect ET−1−evoked responses in the trachea without epithelium. The intravenous administration of ET−1 (1ṁ5nmol kg−1) or ET−3 (1ṁ5 nmol kg−1) evoked a biphasic, fast and sustained bronchoconstriction in anaesthetized guinea-pigs pretreated with propranolol (1ṁ0 mg kg−1). When administered intravenously, RES−701−1 (0ṁ3 or 1ṁ0 mg kg−1) showed significant reduction in both phases of bronchoconstriction induced by ET−3. As in the case of ET−1−induced bronchoconstriction, RES−701−1 augmented the sustained phase although a significant reduction of the fast phase was observed.

These results indicate that RES−701−1 can inhibit the ET−3−induced airway responses not only in-vitro but also in-vivo.
Antitussive Activity of Moguisteine Enantiomers in Guinea-pigs and Rats
Authors: Gallico L , Borghi A , Cavalletti E , Ceserani R , Tognella S
Published: April 2011

The antitussive effect of the R-(+)- and S-(-)-enantiomers of moguisteine were evaluated in comparison with the racemate in cough induced by 7ṁ5% citric acid and 30 μM capsaicin aerosol in conscious guinea-pigs.

No difference in potency was observed between moguisteine and the enantiomers. The oral ED50 values (with 95% confidence limits) for moguisteine, R-(+)- and S-(-)-enantiomers were respectively: 20ṁ4 (12ṁ9−26ṁ6), 20ṁ9 (14ṁ9−26) and 21ṁ6 (11ṁ8−30ṁ0) mg kg−1 in cough provoked by citric acid and 17ṁ7 (12ṁ5−29ṁ8), 18ṁ9 (14ṁ1−30ṁ1) and 20ṁ5 (15ṁ1−36ṁ6) mg kg−1 in cough induced by capsaicin. The acute oral and intraperitoneal toxicities of the enantiomers and moguisteine in the rat are very similar.

These findings suggest that the use of either enantiomer does not offer any advantage over the racemate.
hp, the Component of Log P Controlling Structure-activity Relationships Amongst Non-steroidal Anti-inflammatory Drugs
Authors: Dean Francis M
Published: April 2011

A range of 25 drugs and other compounds selected from published sources by strict criteria, has been used to confirm that their ability to inhibit the production of prostaglandin by mouse peritoneal macrophage does not correlate with log P but with hP, the parameter composed of only the hydrophobic contributions (atoms and groups composed of carbon, hydrogen and halogens). Other heteroatoms and physical properties can usually be ignored.

Anti-inflammatory activity does not depend upon pKa or partition phenomena unless extreme, nor does it depend primarily upon the structural types within the range phenols, salicylic acids, mefenamic acids, areneacetic and profenic acids.
Studies on Powder Plug Formation Using a Simulated Capsule Filling Machine
Authors: Britten Jeffrey R , Barnett Michael I , Armstrong N Anthony
Published: April 2011

Using an apparatus which simulates the action of a Macofar 13-2 dosating-type capsule-filling machine, the variation in plug weight and density with changing machine parameters has been studied.

The piston ejection speed has no effect on plug properties. However increase in compression speed leads to a less consolidated powder plug and hence reduced plug weight. Application of higher pressures reduces plug weight changes, but would be expected to affect release characteristics.

Comparison of axial and radial pressures generated by plugs of Starch 1500 and lubricated lactose show significant differences which can be explained by the different consolidation and elastic properties of the two solids.
Poly-(d,l-Lactic Acid) Microspheres Incorporating Histological Dyes for Intra-pulmonary Histopathological Investigations
Authors: Armstrong D J , Elliott P N C , Ford J L , Gadsdon D , Mccarthy G P , Rostron C , Worsley M D
Published: April 2011

Polylactic acid (PLA) microspheres incorporating fluorescein as a histological marker have been prepared and used as a model for the testing of inhaled PLA microspheres (2–5 μm) in the lung. PLA microspheres (20 mg) were delivered to rabbits in the form of a saline nebulization.

The distribution pattern within the pulmonary system showed that the fluorescein-labelled microspheres were distributed about the four lobes in discrete groups. The comparative numbers of these groups showed a trend towards a reduced concentration in the lower lobes. Subsequent histological examination revealed that the microsphere-treated lungs had been significantly damaged after 24 h.

Histological damage was assessed in terms of pulmonary haemorrhage, eosinophilia and neutrophil infiltration.
Modified β-Cyclodextrin (SBE7-β-CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits
Authors: Jarho Pekka , Järvinen Kristhna , Urtti Arto , Stella Valentino J , Järvinen Tomi
Published: April 2011

The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various β-cyclodextrin (β-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether β-CyD (SBE7-β-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of β-CyD (SBE4-β-CyD and SBE7-β-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-β-CyD (HP-β-CyD) at pH 7:4. Coadministered SBE7-β-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-β-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-β-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-β-CyD solution decreases substantially eye irritation while ocular absorption is not affected.
Uptake and Transport Characteristics of Chloroquine in an In-vitro Cell Culture System of the Intestinal Mucosa, Caco-2
Authors: Augustijns P F
Published: April 2011

The transepithelial transport and uptake of chloroquine were studied in cultured human intestinal Caco-2 cell layers, to investigate whether a specific mechanism facilitates the flux of chloroquine. Due to ionization of chloroquine at the pH of the intestinal lumen, the fraction of the neutral form, which is required for partitioning into biological membranes, is very low, while oral bioavailability has been reported to be nearly complete. Several observations, such as concentration-dependent uptake and temperature-dependent transepithelial flux, suggest the presence of carrier mediated transport. However, alternative mechanisms may be invoked to explain these observations. It is suggested that concentration dependence can originate from ion-trapping in acidic compartments of the cell or non-specific binding to cell components, while temperature-dependent transport can, at least partly, be explained by the temperature dependence of the acid dissociation constants of chloroquine. No differences were observed in the transepithelial flux of the enantiomers of chloroquine. pH-dependent uptake as well as pH-dependent transepithelial transport suggest that the translocation of chloroquine occurs according to the fraction of neutral molecules.

From the data obtained in this study, it is concluded that chloroquine crosses the gastrointestinal barrier by passive diffusion. The extensive area of the gastrointestinal tract probably compensates for the low fraction of the neutral molecule. An interesting finding of this study was the concentration-dependent increase in transepithelial electrical resistance across monolayers incubated with chloroquine at the apical side.
Influence of Plasma-protein Binding on Analgesic Effect of Methadone in Rats with Spontaneous Withdrawal
Authors: Garrido M J , Jiminez R , Gomez E , Calvo R
Published: April 2011

The effect of spontaneous withdrawal on α1-acid glycoprotein (AAG) levels and methadone protein binding has been studied in the rat.

Animals were made physically dependent on morphine by providing morphine HCl in drinking water for three weeks. The natural opiate withdrawal was induced in rats by substituting the morphine solution with drinking water. The severity of the abstinence syndrome was assessed at various time intervals. After 12 h of withdrawal, the animals showing abstinence signs and low morphine levels were injected with intravenous methadone (0.35 mg kg−1) and the analgesic effect was measured by the tail-flick method and compared with animals receiving water.

The oral administration of morphine produced an increase in AAG levels from 0.64 ± 005 g L−1 in control animals to 1.47 ± 0.92 g L−1 in experimental animals at the point of withdrawal and 1.21 ± 009 g L−1 24 h after withdrawal. The percentage of methadone unbound was significantly lower in morphine-treated than in control animals. A significant correlation between AAG levels and percentage of methadone bound was observed. A parallel analgesic effect after intravenous methadone, as measured by AUC in the tail-flick test, was less in abstinence animals than in control (287.6 ± 24.8 compared with 401.0 ± 37.06 s min). We suggest that in the withdrawal syndrome an adjustment of methadone dose may be necessary because of changes in protein binding.
Changes in the Subcellular Distribution of the Rat Uterus Oestrogen Receptor as Induced by Oestradiol, Tamoxifen and ZD 182,780
Authors: Mendes A Ferreira , Caramona M M , Lopes M Celeste
Published: April 2011

The aim of this work was to compare the subcellular distribution of the oestrogen receptor from the uteri of rats treated with vehicle alone (control group), oestradiol or one of the antio-estrogenic drugs tamoxifen and ZD 182,780. The nuclear, microsomal and cytosolic oestrogen receptor contents were evaluated by an immunoenzymatic method (“ER-EIA” kit from Abbott Laboratories) and the results in each fraction were expressed as a percentage of the total number of receptors. Parallel studies were performed to assess the uterotrophic effect of these drugs and to assess that they had reached the uterus.

In the control group, we found that the oestrogen receptor was distributed mainly between the microsomal (29.1 ± 1.3%) and cytosolic (68.1 ±0.9%) fractions, with only a small amount located in the nucleus (2.8 ± 0.5%). When oestradiol was administered, the oestrogen receptor distribution was: nuclear 11.7 ± 2.0, microsomal 15.5 ± 1.3 and cytosolic 72.8 ± 3.3% and, in the tamoxifen group, the results were: nuclear 18.5 ± 1.5, microsomal 26.0 ± 31 and cytosolic 55.5 ± 3.4%, which shows a relative shift both to the control and the oestradiol-treated groups. In the uteri of rats treated with ZD 182,780 the results were very similar to those obtained in the control group.

Our results indicate that the subcellular distribution of the oestrogen receptor varies according to the drug administered and that this receptor may not be located in a single subcellular compartment. Moreover, the nuclear uptake of the ZD 182,780-oestrogen receptor complex seems to be blocked, possibly due to impaired receptor dimerization. In the case of tamoxifen, the intracellular transport of the receptor also seems to be blocked, probably due to the nuclear retention of the receptor, thus suggesting that tamoxifen must impair the oestrogen receptor function on a step subsequent to the receptor dimerization.
Surprising Pharmacological Activity of Analogues Designed by Substitution of Position 3 in Arginine Vasopressin (AVP) and 8-D-Arginine Vasopressin with l-2-Naphthylalanine
Authors: Lammek Bernard , Konieczna Ewa , Trzeciak Henryk I , Kozlowski Artur , Szymkowiak Jacek , Stojko Rafal , Kupryszewski Gotfryd
Published: April 2011

In an attempt to develop more active and selective analogues of arginine vasopressin (AVP), two peptides have been designed, synthesized and tested for vasopressor (V1-receptors) and antidiuretic (V2-receptors) activities. We also estimated the uterotonic and anti-uterotonic activities of these compounds in-vitro.

The first peptide, [(l-2-Nal)3] AVP is a highly active V2-agonist. The second analogue, [(l-2-Nal)3, (d-Arg)8]VP is among the most potent antagonists of the vasopressor response to AVP. Moreover, it is the first V1-antagonist devoid of anti-uterotonic activity.

High antipressor potency of the second peptide was achieved without modification of position 1.
Antihypertensive Drugs Reduce Noradrenaline-induced Hypertrophy of Cultured Myocardial Cells
Authors: Lähteenmäki T A , Sievi E , Vapaatalo H
Published: April 2011

The cellular mechanisms of cardiac hypertrophy are still largely unknown. In-vivo studies have demonstrated that antihypertensive drugs can regress hypertrophy independently of reductions in blood pressure. The antihypertrophic effects of metoprolol, propranolol, felodipine, verapamil and captopril were studied in neonatal cardiac myocyte culture. Prazosin was used as a positive control. Hypertrophy was defined as an increase in protein content measured by [3H]leucine incorporation.

Noradrenaline induced a 1.5-fold increase in protein synthesis over 48 h. Prazosin prevented the hypertrophic effect of noradrenaline. Adrenergic β-receptor blocking agents and calcium antagonists reduced myocyte hypertrophy in a dose-dependent manner. The angiotensin-converting enzyme inhibitor captopril was ineffective.

These results indicate that adrenergic β-receptor blockers and calcium antagonists may have direct nonhaemodynamic effects on the growth of cultured cardiac myocytes.
Preventive Effects of Unsei-in and Oren-gedoku-to, Chinese Traditional Medicines, Against Rat Paw Oedema and Abdominal Constriction in Mice
Authors: Wang L M , Mineshita S
Published: April 2011

Oren-gedoku-to and Unsei-in are complex mixtures of ingredients derived from plants. These two drugs are clinically most frequently used in the treatment of Behçet's disease, we have investigated the anti-inflammatory and analgesic actions of Oren-gedoku-to and Unsei-in using a battery of tests; rat paw oedema induced by five different agents; abdominal constriction; mouse ear swelling; and dye leakage tests, designed to clarify the therapeutic potential of these medicines.

The findings in this study that these medicines are able to inhibit the rat paw oedema, suppress the abdominal constriction and inhibit the increased dye permeability confirm the analgesic and anti-inflammatory effects of these compounds.

From these results there seems a clear rationale for exploring the effectiveness of these Chinese medicines in the treatment øf chronic and acute inflammatory diseases.