bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Potassium-channel Opener HOE 234 in Guinea-pig Airways
Authors: Redemann B , Vaali K , Li L , Paakkari I , Vapaatalo H
Published: April 2011

The mechanism of the bronchospasmolytic effect of HOE 234 ((3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-phenylsulphonylchromane hemihydrate), a novel opener of ATP-sensitive potassium channels, has been studied by in-vitro testing in ring preparations of trachea and different parts of the principle bronchus of guinea-pigs, using methacholine, histamine and KCl as preconstrictors. The contribution of prostanoids was estimated in the presence and absence of indomethacin. Regional differences in the bronchodilatory effect of HOE 234 were compared with that of salbutamol.

HOE 234 had a concentration-dependent relaxing effect on the smooth muscle preparations. In the absence of indomethacin no regional differences were seen for the effect of HOE 234 against the metacholine or KCl preconstriction, whereas with histamine a particularly strong relaxation was detectable in trachea. In the presence of indomethacin, distal bronchus after methacholine and trachea after KCl preconstriction were relaxed significantly more strongly than the other parts. The relaxation of the histamine-constricted trachea rings was not increased in comparison with that without indomethacin pretreatment. Thus the bronchospasmolytic effect of HOE 234 varied depending on the pretreatment, method of preconstriction and part of the airways examined. It was strongest in trachea rings with histamine preconstriction but its potency was clearly less than that of salbutamol. The latter had regionally different effects, being stronger in trachea than in the bronchi for all methods of preconstriction.

The results suggest that the formation of bronchoconstricting prostanoids can attenuate parts of the relaxing effect of HOE 234. The possible advantages of HOE 234 as an anti-asthma drug might be related to an effect on bronchial hyper-reactivity and mucus secretion, because as a direct bronchodilator it is inferior to salbutamol.
Poly(alkyl cyanoacrylate) Nanocapsules as a Delivery System in the Rat for Octreotide, a Long-acting Somatostatin Analogue
Authors: Damgé Christiane , Vonderscher Jacky , Marbach Peter , Pinget Michel
Published: April 2011

Poly(alkyl cyanoacrylate) nanocapsules have been used as biodegradable polymeric drug carriers for subcutaneous and peroral delivery of octreotide, a long-acting somatostatin analogue; their ability to reduce insulin secretion or prolactin secretion in response to oestrogens has been studied in adult male rats.

The nanocapsules, prepared by interfacial emulsion polymerization of isobutyl cyanoacrylate, were 260 nm in diameter and incorporated 60% of octreotide. Administered subcutaneously, the octreotide-loaded (20 μg kg−) nanocapsules suppressed the insulinaemia peak induced by intravenous glucose overload and depressed insulin secretion over 48 h, preventing the secretory rebound; however, glycaemia was unaffected. In parallel, the plasma octreotide concentration increased 2.7 times. Administered perorally to oestrogen-treated rats, octreotide-loaded nanocapsules (200 and 1000 μg kg−) significantly improved the reduction of prolactin secretion (by 72 and 88%, respectively, compared with 32 and 54% with free octreotide) and slightly increased plasma octreotide level.

Thus nanocapsules could be of interest as a biodegradable drug carrier for the administration of octreotide.
Inhibition of Potassium (KATP) Channels Reduces the Short-circuit Current Response of Rat Colonic Mucosa to Acetylcholine
Authors: Darko S K A , Palmerley N D , Burleigh D E
Published: April 2011

Intestinal secretion depends upon electrogenic chloride transport into the gut lumen, which requires maintenance of an electrically negative cell-membrane voltage. We have investigated whether secretory responses of rat colonic mucosa to acetylcholine were sensitive to inhibition of potassium channels and whether selective inhibition could indicate the nature of the channel involved.

Rat colonic mucosa was set up in Ussing chambers, short-circuit current responses obtained to acetylcholine, and the sensitivity of such responses to inhibition of potassium channels was investigated. Non-selective potassium-channel blockade by barium induced concentration-dependent inhibition of responses to acetylcholine. Similar inhibitory effects were obtained using 4-aminopyridine and glibenclamide. 5-Hydroxydecanoate and phentolamine also inhibited the increase in short-circuit current. However, a combination of charybdotoxin plus apamin was without effect.

We conclude that a basolateral outward movement of potassium ions is required for the secretory action of acetylcholine on rat colonic mucosa. The potassium channel involved seems to be ATP-dependent and calcium-insensitive.
Effect of Policosanol on Circulating Endothelial Cells in Experimental Models in Sprague-Dawley Rats and in Rabbits
Authors: Noa MIRIAM , Más Rosa , Mesa Rosario
Published: April 2011

The effect of policosanol on circulating endothelial cells has been studied in different experimental models with endothelium damage.

Oral administration of 25 mg kg− policosanol to Sprague-Dawley rats resulted in significant protection of the endothelial lining against the desquamating effect of citrate. Oral administration of 5 mg kg− policosanol to spontaneously hypertensive rats (SHR) resulted in a significant reduction of circulating endothelial cells compared with controls. Moreover, comparison between groups revealed a lower frequency of aortic lesions in policosanol-treated animals than in controls. On the other hand, administration of 5 mg kg− policosanol to rabbits with intimal hyperplasia induced by cuff placement in the carotid artery resulted in levels of circulating endothelial cells significantly lower than in controls.

These results demonstrate the protective effect of policosanol in different experimental models and suggest its potential for endothelial protection.
A Xanthanolide with Potent Antibacterial Activity against Methicillin-resistant Staphylococcus aureus
Authors: Sato Youichi , Oketani Hideki , Yamada Tomoko , Singyouchi Ken-Ichi , Ohtsubo Tetsuya , Kihara Masaru , Shibata Hirofumi , Higuti Tomihiko
Published: April 2011

This study was conducted to find constituents of an annual herb, Xanthium sibiricum Patr er Widd, with effective antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

By monitoring antibacterial activity against MRSA strains, it was shown that a sesquiterpene lactone, identified as [3aR-(3aα,7β,8aβ)]-3,3a,4,7,8,8a-hexahydro-7-methyl-3-methylene-6-(3-oxo-1-butenyl)-2H-cyclohepta[b]furan-2-one, or xanthatin, isolated from leaves of the herb, had outstandingly potent activity against S. aureus species, including MRSA; its activity against MRSA and MSSA strains was similar. Other bacteria, e.g. Staphylococcus epidermidis, Klebsiella pneumoniae, Bacillus cereus, Pseudomonas aeruginosa and Salmonella typhi, were also susceptible at the concentrations tested but the compound had no inhibitory effect on some other bacteria, including Escherichia coli.

The results show that xanthatin has outstandingly potent activity against strains of S. aureus but that the activity of the compound is highly species-specific.
Inhibition of the Hepatic Uptake of Paracetamol Sulphate by Anionic Compounds
Authors: Sakuma-Sawada Noriko , Iida Satofumi , Mizuma Takashi , Hayashi Masahiro , Awazu Shoji
Published: April 2011

The effect of anionic compounds on the hepatic uptake of paracetamol sulphate, a conjugative metabolite of paracetamol, has been studied.

Hepatic uptake of paracetamol sulphate by isolated hepatocytes was inhibited by bromosulphophthalein, dibromosulphophthalein and p-nitrophenyl sulphate, but not by probenecid or cholic acid. Bromosulphophthalein and dibromosulphophthalein also inhibited the uptake of paracetamol sulphate in the rat isolated perfused liver. Saturable uptake of paracetamol sulphate was also observed in the absence of inorganic sulphate. The uptake of paracetamol sulphate was reduced by 1 and 10 mm inorganic sulphate. Bromosulphophthalein and p-nitrophenyl sulphate inhibited the uptake of paracetamol sulphate in the absence of inorganic sulphate.

These results indicate that paracetamol sulphate shares a transporter with bromosulphophthalein, dibromosulphophthalein and p-nitrophenyl sulphate, all of which contain the sulphate or sulphonate group. Therefore, the sulphate or sulphonate moiety might be crucial for interaction with the transporter, and mutual inhibition of hepatic uptake among these compounds is likely.
High-performance Thin-layer Chromatography for the Determination of Nimesulide in Human Plasma, and its Use in Pharmacokinetic Studies
Authors: Pandya K K , Satia M C , Modi I A , Modi R I , Chakravarthy B K , Gandhi T P
Published: April 2011

A rapid and sensitive high-performance thin-layer chromatographic assay has been developed for the measurement of nimesulide in human plasma. Its use for pharmacokinetic studies has been evaluated.

The method includes a single-stage extraction procedure without the use of an internal standard. Analysis was performed on plasma containing known amounts of the drug, on drug-free plasma, and on plasma containing an unknown quantity of the drug. Known amounts of extract and nimesulide (100 and 200 ng, as external standard) were spotted on precoated silica-gel 60F254 plates by means of a Camag Linomat IV autosampler. Quantification was achieved using a Camag TLC scanner 3. The recovery of the method was 97.10 ± 2.22%. The method was applied for the determination of plasma levels and pharmacokinetic parameters of nimesulide after oral administration of two formulations (100 mg) in healthy volunteers.

The method is a sensitive, economical, rapid and specific assay for nimesulide in human plasma, and is suitable for pharmacokinetic studies after therapeutic doses.
Protective Effects of Dilazep and its Derivative K-7259 on the Haemolysis Induced by Amphiphiles in Rat Erythrocytes
Authors: Hara Akiyoshi , Hayase Nobumasa , Hashizume Hiroko , Abiko Yasushi
Published: April 2011

The effects of dilazep and K-7259, a dilazep derivative, on the haemolysis (as evidenced by release of haemoglobin) induced by palmitoyl-l-carnitine (PAL-CAR) or palmitoyl 1-α-lysophosphatidylcholine (PAL-LPC) have been determined in rat erythrocytes.

At concentrations above the critical micelle concentration both PAL-CAR and PAL-LPC induced haemolysis; the concentrations of PAL-CAR and PAL-LPC producing 50% haemolysis were approximately 13 and 14 μm, respectively. The 50% haemolysis induced by PAL-CAR or PAL-LPC was attenuated by dilazep (1, 10 or 100 μm) but not at the highest concentration used (1 mm). K-7259 attenuated the 50% haemolysis induced by PAL-CAR or PAL-LPC at concentrations ranging from 1 μm to 1 mm. Similarly, dilazep (1 to 100 μm) and K-7259 (1 μm to 1 mm) significantly or insignificantly attenuated the 25% and 75% haemolysis induced by PAL-CAR or PAL-LPC. Neither dilazep nor K-7259 affected micelle formation by PAL-CAR or PAL-LPC, nor, at concentrations of 1 and 10 μm, did they attenuate the haemolysis induced by osmotic imbalance (hypotonic haemolysis).

These results suggest that both dilazep and K-7259 protect the erythrocyte membrane from the damage induced by PAL-CAR or PAL-LPC. The protective effects of dilazep and K-7259 are mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance.
A Comparative Study of Aminophylline- and Acepifylline-induced Seizures and Death in the Chemoconvulsion Model in Rats
Authors: Chakrabarti Amitava , Saini Harsimrat Kaur , Garg Santosh Kumar
Published: April 2011

The convulsive, pro-convulsive and lethal effects of two theophylline-containing bronchodilating agents, aminophylline and acepifylline, have been evaluated in rats.

Aminophylline (theophylline ethylenediamine) caused seizures and death in a dose-dependent manner; an intraperitoneal dose of 250 mg kg− caused seizures and death in all rats. Intraperitoneal doses of acepifylline (theophylline ethanoate of piperazine) up to 1000 mg kg−, however, did not cause seizure or death. Further, pre-treatment of the rats by intraperitoneal administration of a subconvulsive dose (100 mg kg−) of aminophylline caused a significant decrease in CD50 and LD50 values for pentylenetetrazole and a significant increase in the number of positive responders (i.e. rats with a pentylenetetrazole-induced seizure score of 3 or more on a seizure scale ranging from 0 to 6) and death rate compared with those obtained for rats pre-treated with an equivalent intraperitoneal dose (140 mg kg−) of acepifylline (‘equivalent dose’ referred to here denotes the theophylline content of the two preparations).

The study has established the neurosafety profile of acepifylline and documents a safer alternative to aminophylline for use in asthmatics suffering from concomitant epilepsy or other seizure-prone neurological defects.
Effects of Flavonoids Isolated from Scutellariae Radix on the Production of Tissue-type Plasminogen Activator and Plasminogen Activator Inhibitor-1 Induced by Thrombin and Thrombin Receptor Agonist Peptide in Cultured Human Umbilical Vein Endothelial Cells
Authors: Kimura Yoshiyuki , Yokoi Kumi , Matsushita Nobutoshi , Okuda Hiromichi
Published: April 2011

The effects of different flavonoids isolated from the roots of Scutellaria baicalensis Georgi on the production of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) induced by thrombin and thrombin receptor agonist peptide, Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe, have been examined in cultured human umbilical vein endothelial cells (HUVECs).

Thrombin and thrombin receptor agonist peptide induced production of both t-PA and PAI-1 and the elevation of intracellular free calcium concentration ([Ca2+]i). Baicalein isolated from Scutellariae Radix dose-dependently inhibited PAI-1 production induced by thrombin and thrombin receptor agonist peptide; its concentrations for 50% inhibition (IC50) were 6.8 and 3.5 μm, respectively. Other flavonoids had no effect. In contrast, flavonoids isolated from Scutellariae Radix had no effect on production of t-PA induced by thrombin and thrombin receptor agonist peptide. Baicalein inhibited the elevation of [Ca2+]; induced by thrombin and thrombin receptor agonist peptide and, at a concentration of 1000 μm, slightly increased t-PA production.

These findings suggest that the mechanism by which baicalein inhibits PAI-1 production induced by thrombin and thrombin receptor agonist peptide might be by reduction of [Ca2+]i elevation. The results suggest that baicalein in Scutellariae Radix might be active as a drug in the treatment of arteriosclerosis and thrombosis.
Effect of Formulation on the Rheology of Theophylline Compound Suspensions in Gelucires
Authors: Ratsimbazafy V , Bourret E , Brossard C
Published: April 2011

The theophylline derivatives, etofylline, diprophylline and proxyphylline, which exhibit increasing aqueous solubitity, were used to prepare suspensions in seven saturated polyglycolysed glycerides (Gelucires) characterized by their rising hydrophilic-lipophilic balance (HLB). Drug concentration was set at 25% w/w and the production temperature was set at the Gelucire melting point plus 30°C in order to obtain suitable suspensions. Various formulation factors were studied.

Ostwald flow indices revealed that the suspensions had a thixotropic shear-thinning behaviour and a relative viscosity which increased as drug aqueous solubility rose and Gelucire HLB decreased. These rheological properties could be explained by the chemical composition of Gelucires and drugs used.

A microstructure was proposed for the liquid suspension such that colloidal particles and aggregates formed in these suspensions directly influenced the observed rheological properties. Observation of solidified suspensions by scanning electron microscopy confirmed this hypothesis. Moreover, a correlation between the relative viscosity of drug suspensions on the one hand and drug concentration, drug solubility and Gelucire HLB on the other allowed for the calculation of the required concentration of each theophylline derivative in each Gelucire to obtain a given viscosity.
Effects of Trecadrine, a β3-Adrenergic Agonist, on Intestinal Absorption of d-Galactose and Disaccharidase Activities in Three Physiopathological Models
Authors: Diez-Sampedro Ana , Milagro Fermin I , Berraondo Beatriz , Zulet Maria A , Martinez J Alfredo , Barber Ana
Published: April 2011

Impairments in intestinal absorptive and digestive processes have been described in several pathophysiological situations, such as in drug-induced diabetes, obesity and hypercholesterolaemia. Furthermore, there is evidence for the occurrence of β3-adrenoceptors in multiple regions of the gastrointestinal tract, but there are no data concerning their possible involvement on jejunal and ileal digestive and absorptive functions. In this work, we have measured the modifications of selective intestinal absorption and disaccharidase activities in alloxan-induced diabetic and in diet-induced obese and hypercholesterolaemic Wistar rats. The action of a β3-adrenergic agonist (Trecadrine) with hypoglycaemic and lipolytic properties on those gastrointestinal functions has been studied.

Increases in the galactose uptake by intestinal rings and in both sucrase and maltase activities were found in diabetic rats. The results obtained after Trecadrine administration to diabetic rats led to an improvement of the altered values. On the other hand, our data show a decrease in sugar absorption and in disaccharidase activities in both obese and hypercholesterolaemic groups, probably related to the low carbohydrate and high fat content of these diets. An amelioration in sucrase activity was observed after treatment with Trecadrine. Finally, Trecadrine administration to control animals significantly inhibited galactose intestinal absorption, which was independently confirmed by additional in-vitro studies.

Overall, these results could be attributed not only to an improvement in the pathophysiological condition (diabetes, obesity and hypercholesterolaemia), but also to a direct effect of the β3-adrenergic agonist on the intestinal absorption processes.
Effect of Plaunotol on Gastric Injury Induced by Ischaemia-Reperfusion in Rats
Authors: Wada Kouichirou , Kamisaki Yoshinori , Nakamoto Kentaro , Kishimoto Yosuke , Ashida Kumiyo , Itoh Tadao
Published: April 2011

Plaunatol, an anti-ulcer drug, increases prostaglandin content in gastric tissue but its effect on radical-mediated gastric damage or activity against reactive oxygen species is unknown. We examined the effects of oral administration of plaunotol (Kelnac) on the acute gastric mucosal lesion and its progression to ulcer lesion induced by ischaemia-reperfusion in rats.

Plaunotol (30 and 100 mg kg−, 15 min before ischaemia) significantly reduced the total erosion area observed immediately after ischaemia-reperfusion. When plaunotol (30 and 100 mg kg−, once a day) was administrated orally 60 min after reperfusion, it prevented the progression from erosion to ulcer. At 72 h after ischaemia-reperfusion, the total area of ulcers lesions was significantly reduced compared with that without plaunotol administration. Furthermore, treatment with plaunotol (100 mg kg−) significantly increased prostaglandin E2 content in gastric tissues of both acute gastric mucosal lesion and gastric ulcer lesion. In in-vitro experiments, plaunotol (1–3 mg mL−) reduced the superoxide radicals generated by leucocytes, but not by xanthine oxidase.

These results indicate that plaunotol has protective effects on both the onset of acute gastric mucosal injury and its progression to ulcer lesion induced by ischaemia-reperfusion.

Both effects of plaunotol on increase in prostaglandin content in gastric tissues and inhibition of superoxide radical from leucocytes may play important roles on the protection against gastric mucosal injury.
Stability Behaviour of Molsidomine-containing Pellet Formulations
Authors: Laicher A , Jünger H , Klemm F H
Published: April 2011

Molsidomine in mixtures with different inactive ingredients has been subjected to a stability test.

The fingerprint chromatogram obtained by HPLC with diode-array detection of mixtures of molsidomine with povidone 25 revealed decomposition products; the detection wavelength of 210 nm resulted in easy detection of the degradation products. Molsidomine-containing pellets were manufactured according to a compact procedure and by applying the active ingredient to placebo pellets. Compared with the nonpareil pellet formulations, compact pellets have a considerably higher water content and undergo decomposition of the active ingredient after storage for 50 months under different conditions.

It is assumed that the decomposition of molsidomine is accelerated by the peroxide found in povidone.
ZD9583, an Orally Effective Thromboxane A2 Synthase Inhibitor and Receptor Antagonist with a Sustained Duration of Action in Rat and Dog
Authors: Brownlie R P , Brownrigg N J , Butcher H M , Garcia R , Jessup R , Lee V J , Tunstall S , Wayne M G
Published: April 2011

The thromboxane A2 (TXA2) synthase inhibitory activity and the TXA2 receptor (TP-receptor) blocking action of ZD9583 ((4Z)-6-[(2S,4S,5R)-2-(1-[2-cyano-4-methylphenoxy]-1-methylethyl)-4-(3-pyridyl)-1,3-dioxan-5-yl]hex-4-enoic acid) has been evaluated in-vitro by use of whole blood and platelets from man, and ex-vivo by use of platelets and whole blood from rats and dogs.

ZD9583 caused concentration–dependent inhibition of human platelet microsomal TXA2 production with an IC50 of 0.017 ± 0.003 μm; this inhibition was associated with an increase in prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) formation. ZD9583 also inhibited collagen-stimulated TXA2 synthesis in whole blood from man, rat and dog giving IC50 values of 0.027 ± 0.005, 0002 ± 0.006 and 0.013 ± 0.01 μm, respectively. The drug did not modify platelet cyclooxygenase activity as inhibition of thromboxane B2 (TXB2) formation was associated with a concomitant increased synthesis of prostaglandin D2 (PGD2), PGE2 and PGF2α. ZD9583 had little effect on cultured human umbilical vein endothelial cell prostacyclin synthase giving an IC50 of 24.2 ± 4.9 μm. In-vitro ZD9583 caused concentration-dependent inhibition of U46619-induced aggregation responses of platelets from man, rat and dog, yielding apparent log A2 values of 8.7 ± 0.12, 8.8 ± 0.2 and 9.3 ± 0.2, respectively. The drug was selective; at concentrations up to 100 μm it did not affect 5-hydroxytryptamine or the primary phases of adenosine diphosphate and adrenaline-induced aggregation. ZD9583 (100 μm) did not, furthermore, modify the platelet inhibitory effects of PGD2, prostaglandin E1 (PGE1) and prostacyclin. Oral administration of ZD9583 (3–10 mg kg−1) to both rats and dogs caused dose-dependant inhibition of collagen-stimulated TXA2 production ex-vivo which persisted for up to 12 h. The drug also caused profound TXA2 receptor blockade in both species for in excess of 12-h after an oral dose of 3 mg kg−1. ZD9583 (3 mg kg−1, p.o.), when administered to dogs over a five-day period at 12 h intervals, did not cause either tachyphylaxis or an accumulation of effect.

We conclude that ZD9583 is a potent, selective, orally active thromboxane synthase inhibitor and TXA2 receptor antagonist.
Stereoselective N-Demethylation of Chlorpheniramine by Rat-liver Microsomes and the Involvement of Cytochrome P450 Isozymes
Authors: Nomura Akio , Sakurai Eiichi , Hikichi Noboru
Published: April 2011

Previous studies have suggested that degradation of the two stereoisomers of chlorpheniramine in the liver might be catalysed by different types of cytochrome P450. Stereoselective N-demethylation of chlorpheniramine and the involvement of cytochrome P450 (CYP) isozymes have, therefore, been investigated in the liver microsomes of eight-week-old male rats.

Incubation of racemic chlorpheniramine with liver microsomes from the male rat resulted in the formation of both enantiomers of monodesmethylchlorpheniramine (DMChp). Further metabolism of DMChp to didesmethylchlorpheniramine (DDMChp) did not, however, occur. The S/R enantiomeric ratio for intrinsic clearance (Vmax/Km) was approximately 2.0, suggesting that the N-demethylation was stereoselective for S-(+)-chlorpheniramine. On the other hand, although the Vmax/Km value for the formation of S-(+)- and R-(–)-DMChp increased with phenobarbitone-inducible rat-liver microsomes, there was no difference between the rates of N-demethylation of the enantiomers. In contrast, 3-methylcholanthrene reduced the intrinsic clearance of S-(+)-chlorpheniramine by N-demethylation and increased its value for R-(–)-chlorpheniramine, showing no stereoselectivity for the N-demethylation of chlorpheniramine. The difference between the intrinsic clearance of the two enantiomers by N-demethylation was because of differences in affinity for the catalysing enzyme. This is indicative of stereoselective involvement of the main enzyme concerned in the N-demethylation of the enantiomers, considered to be CYP 2C11. Anti-CYP 2C11 also partially inhibited the N-demethylation of racemic chlorpheniramine in rat-liver microsomes exposed to phenobarbitone and 3-methylcholanthrene. That CYP 2B1 was involved in the N-demethylation of both enantiomers was also supported by results from an experiment using phenobarbitone-inducible rat-liver microsomes. CYP1A1 did not, however, catalyse the N-demethylation of either enantiomer.

These results indicate that N-demethylation of the S-(+)-enantiomer of chlorpheniramine occurs preferentially in the microsomes, demonstrating the stereoselective contribution of CYP2C11. Immunoinhibition studies suggest, moreover, that the N-demethylation of both chlorpheniramine enantiomers is catalysed by CYP2B1, but not by CYP1A1.
Optimization of the Chiral Inversion of 2-Phenylpropionic Acid by Verticillium lecanii
Authors: Thomason Michael J , Rhys-Williams William , Lloyd Andrew W , Hanlon Geoffrey W
Published: April 2011

Previous studies have demonstrated that Verticillium lecanii might be used as a microbial model of the inversion of 2-arylpropionic acids in man. This paper describes the optimization of the inversion process in respect of culture medium, pH, cell density and substrate concentration.

The study demonstrates that optimum inversion occurs in Sørensen's phosphate buffer at pH 5.5. The extent and rate of inversion were also shown to be dependent on substrate concentration and cell density.

This study will form the basis of the development of a microbial model of the metabolism of 2-arylpropionic acids which might be suitable for the in-vitro screening of new compounds in this class.
Pharmacokinetics of Heterologous and Homologous Immunoglobulin G, F(ab‘)2 and Fab after Intravenous Administration in the Rat
Authors: Bazin-Redureau Martine I , Renard Catherine B , Scherrmann Jean-Michel G
Published: April 2011

Because few pharmacokinetic studies of antibodies and their fragments have compared the influence of species origin and antibody size, the plasma pharmacokinetics of a single intravenous dose (0.7 mg kg−1) of 125I-labelled mouse, rat and human immunoglobulin G (IgG), and mouse F(ab')2 and Fab were investigated in the rat.

IgG reached equilibrium after six distribution half-lives, i.e. only 36–50 h post-dosing, and the distribution volume was about four times the rat plasma volume. IgG elimination half-lives ranged from 5.33 to 8.10 days. Fragmentation of IgG into smaller fragments, F(ab')2 and Fab, resulted in pharmacokinetics that were molecular-weight-dependent with volume of distribution and systemic clearance values inversely related to antibody size.

We conclude that antibody variability in terms of species origin and size influences antibody pharmacokinetics and should be carefully studied before selection of the best antibody for a clinical application.
The Effect of the Calcium Antagonist Nimodipine on the Detoxification of Soman in Anaesthetized Rabbits
Authors: Karlsson Britt M , Waara Lena M , Fredriksson Sten-Åke , Koskinen Lars-Owe D
Published: April 2011

The effect of nimodipine, a vasoactive calcium antagonist, on the disappearance of soman from blood was studied in anaesthetized rabbits intoxicated with soman (10.8 μg kg−1 i.v.). Blood samples from the left heart ventricle and femoral artery were used to investigate soman detoxification. The concentrations of the soman isomers C + P - and C - P - in blood samples were determined by gas chromatography coupled with high-resolution mass spectrometry.

During the sampling, 15–300 s after soman injection, the soman concentration in control animals decreased from 50 to 0.029 ng mL−1; in animals pre-treated with nimodipine (10 mg kg−1) it decreased from 15 to 0.033 ng mL−1. In animals pre-treated with nimodipine the soman concentration was significantly reduced during the first minute of sampling. No differences were detected between soman concentrations in samples from the heart and femoral artery. Acetylcholinesterase inhibition was also used as an indicator of soman activity; there was no difference between the activity of this enzyme in different peripheral organs of control and nimodipine-treated animals.

Nimodipine reduces the initial concentration of soman in the blood, which might be of significance in the treatment of soman intoxication.
A Sensitive Assay for Studying Dopaminergic Activity in Cultures of Rat Pituitary Cells
Authors: Giacomelli Sabrina , Braghiroli Laura , Ponzianelli Anna , Koppenaal Dirk W , De Feo Giuseppe
Published: April 2011

The dopaminergic and antidopaminergic activity of drags is frequently assayed in pituitary cell cultures. Here we describe a modified version of the assay based on the use of pituitary cells from prepubertal female rats.

Under our experimental conditions (50000 cells well−1, 2-day culture and 2-h drug-exposure) the assay yielded high selectivity and sensitivity for drug dopaminergic activity. D2 agonistic activity of bromocriptine could be observed at a concentration as low as 10−15 m, the antagonistic activity of haloperidol at 10−16 m. The assay also proved reproducible and simple enough for routine screening of dopaminergic activity.

The assay enabled dopaminergic agonist and antagonist activity to be revealed at very low drug concentrations. The high sensitivity of the assay could be of advantage in studying dopaminergic activity in samples containing active substances present at low concentrations or for disclosing the activity of substances with low dopaminergic potency.
Influence of Certain Calcium-channel Blockers on Some Aspects of Lorazepam-dependence in Mice
Authors: Saad Samir F , Khayyal M T , Attia Amina S , Saad Ehab S F
Published: April 2011

The effect of acute and chronic treatments of the calcium-channel blockers, isradipine, diltiazem and flunarizine in protecting against lorazepam dependence has been demonstrated in mice.

Dependence was induced by twice-daily administration of lorazepam (1 mg kg−1) for 10 days, doubling the dose during the next 10 days. Withdrawal symptoms

and changes in the noradrenaline, dopamine and 5-hydroxytryptamine content of different regions of the brain were observed after either 24-h withdrawal or flumazenil administration. Isradipine inhibited lorazepam withdrawal symptoms, the effect being accompanied in the 24-h withdrawal group by significant decreases in the noradrenaline and dopamine content of the thalamus and hypothalamus and in the noradrenaline content of the mid-brain. In the flumazenil-treated group isradipine produced significant decreases in mid-brain noradrenaline and dopamine levels and in the dopamine content of the thalamus and hypothalamus. Diltiazem did not, on the other hand, afford significant protection against lorazepam withdrawal symptoms and did not induce any significant change in the neurotransmitters studied. Flunarizine significantly inhibited lorazepam withdrawal symptoms, an effect accompanied by significant reduction in noradrenaline and dopamine levels in the thalamus and hypothalamus. Dopamine was also significantly reduced in the cerebral cortex. Similar effects were produced in the flumazenil-treated group, and the noradrenaline content was reduced in the medulla, pons and cerebellum.

It was concluded that isradipine and flunarizine might be of value in ameliorating lorazepam withdrawal symptoms.
A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin
Authors: Kelder Jan , Funke Carel , de Boer Thus , Delbressine Leon , Leysen Dirk , Nickolson Victor
Published: April 2011

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated.

Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin.

The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.
Behavioural Subsensitivity Induced by Long-term Administration of a Low Dose of Haloperidol to Rats
Authors: Frussa-Filho Roberto , Abílio Vanessa Costhek , Bergamo Marcelo , Palermo-Neto João
Published: April 2011

This study examines the effects on open-field and stereotyped behaviour of rats of abrupt withdrawal from repeated treatment with a low (0.03 mg kg−1) dose of haloperidol.

Single administration of this low dose of haloperidol significantly increased open-field locomotion without modifying apomorphine (0.5 or 2.0 mg kg−1)-induced stereotyped behaviour. Forty-eight hours after abrupt withdrawal from 0.03 mg kg−1 haloperidol (twice daily for 15 days) a significant decrease in locomotion frequency was observed, but no change was observed in apomorphine-induced stereotypy.

Our results suggest that dopamine autoreceptor supersensitivity might be evaluated in a behavioural situation of absence of postsynaptic dopamine receptor supersensitivity.
Antihypertensive Effect of some Oxazolo[3,2-a]pyridines, Thiazolo[3,2-a]pyridines and Pyrido[2,1-b]oxazines in Conscious Spontaneously Hypertensive Rats
Authors: Moran Asunción , Martín Elena , Velasco Cristina , Martín M Luisa , Roman Luis San , Caballero Esther , Puebla Pilar , Medarde Manuel , Feliciano Arturo San
Published: April 2011

The antihypertensive activity of eighteen oxazolo[3,2-a]pyridine, fhiazolo[3,2-a]pyridine and pyrido[2,1-b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference.

At a dose of 50 mg kg−1 (i.p.) eleven compounds resulted in a significant reduction in mean arterial blood pressure; four of the eleven were particularly effective, resulting in significant hypotension more than 6 h after administration and an effect that was still apparent after 24 h. The hypotension induced by nifedipine gradually decreased, disappearing 6–8 h after administration. The long-lasting activity shown by these compounds is, in general, not accompanied by reflex tachycardia. Intraperitoneal administration of two oxazolo[3,2-a]pyridine derivatives and two pyrido[2,1-b]oxazine derivatives resulted in potent and long-lasting antihypertensive action in SHRs.

Further studies on the mechanism of action of these derivatives might help the determination of better structure–activity correlations and the design, synthesis and evaluation of better antihypertensive agents.
Prediction of the Plasma Concentration Profiles of Orally Administered Drugs in Rats on the Basis of Gastrointestinal Transit Kinetics and Absorbability
Authors: Sawamoto Taiji , Haruta Shunji , Kurosaki Yuji , Higaki Kazutaka , Kimura Toshikiro
Published: April 2011

A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats.

The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems.

We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.
Something in the Air: Endotoxins and Glucans as Environmental Troublemakers
Authors: Young R S , Jones A M , Nicholls P J
Published: April 2011

This review provides a clear explanation of the current status of two common airborne contaminants, lipopolysaccharide and (1.3)-β-D-glucan, in the induction of indoor air-related disease.

A full description of the origin of these two products is given together with information of their structure and function. Details of the biochemical mechanisms by which they interact with human cells and the physiological consequences of these interactions are outlined.

Both compounds play a key role in the induction of airway inflammation and this paper highlights the environmental importance in the work place and home of these inhaled agents in terms of respiratory disease.
Absorption Studies of Albendazole and Some Physicochemical Properties of the Drug and Its Metabolite Albendazole Sulphoxide
Authors: Jung H , Medina L , García L , Fuentes I , Moreno-Esparza R
Published: April 2011

In several studies of patients with neurocysticercosis under treatment with albendazole the pharmacokinetic data were difficult to interpret, probably because of slow and erratic drug dissolution response and absorption problems in-vivo. Because there is no information available about the physicochemical properties of the drug, the aim of this work was to explain this erratic behaviour by fully characterizing the solution behaviour of the drug and its metabolite. To accomplish this, the physicochemical properties, pKa and solubility, and in-vitro plasma binding of albendazole and its main metabolite, albendazole sulphoxide, were studied by conventional methods. The intestinal and gastric absorption and dissolution behaviour of albendazole were also studied.

The solubility of both compounds is very low. Both are amphoteric molecules with two ionization steps, with pKa values of 10.26 and 2.80 for albendazole and 9.79 and 0.20 for albendazole sulphoxide; low pKa values were obtained by performing linear free energy relationship calculations. On the other hand, protein binding studies showed that albendazole is 89–92% bound to plasma proteins whereas for albendazole sulphoxide the figure is 62–67%. This metabolite is bound by albumin and to α1-glycoprotein. Absorption of albendazole occurs along the gastrointestinal tract and is limited by its solubility. Good dissolution profiles were observed when 0.1 M HCl was used as dissolution medium.

The results show that 0.1 M HCl enables discrimination between the drug-release characteristics of different products.
Circadian Variations in the Pharmacokinetics of Pentoxifylline in Man
Authors: Srinivasu P , Rao B Ramesh , Rao Y Madhusudhan , Rambhau D
Published: April 2011

Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and diseased subjects is manifested as circadian rhythms in blood pressure, cardiac output, heart rate, etc. The disposition of several cardiovascular drugs in man has been reported to be time-dependent. This study reports the effect of time of administration on the disposition of pentoxifylline.

Twelve healthy volunteers were treated with 400 mg pentoxifylline orally at 0100, 0700, 1300 and 1900 h in a randomized crossover Latin-square design with a wash-out period of one week. Serum samples were analysed for unchanged pentoxifylline by HPLC. Pharmacokinetic parameters were calculated using a model-independent method. The mean values of various pharmacokinetic parameters after drug treatment at these times were, respectively: maximum plasma concentration (Cmax) 485 ± 174, 646 ± 175, 735 ± 271 and 781±217 ng mL−1; time to reach the maximum plasma concentration (Tmax) 1.90±0.39, 1.66±0.4, 1.31 ± 0.41 and 1.32 ± 0.44 h, mean residence time (MRT) 3.8 ± 0.8, 2.9 ± 0.5, 2.9 ± 0.4 and 2.7 ± 0.3 h, elimination half-life (t1/2) 1.93 ± 0.86, 1.23 ± 0.3, 1.39 ± 0.3 and 1.23 ± 0.18 h and volume of distribution at steady state (Vdss/f) 11991 ± 4862, 8823 ± 3484, 8275 ± 2357 and 7063 ± 1950 mL kg−1. The mean Cmax value was significantly (P < 0.05) lower after drug administration at 0100 h than after other time-points whereas mean Tmax, MRT, Vdss/f and t1/2 values were significantly (P < 0.05) higher.

These variations might be because of time-dependent changes in absorption and biliary excretion of pentoxifylline and should be borne in mind when designing sustained action dosage forms for the drug.
Cytotoxicity of Absorption Enhancers in Caco-2 Cell Monolayers
Authors: Sakai Michinori , Imai Teruko , Ohtake Hiroshi , Otagiri Masaki
Published: April 2011

This study was performed to evaluate the utility of absorption enhancers with reference to mucosal cell cytotoxicity. Overall assessment of the damage to plasma, lysosomal and nuclear membranes by three absorption enhancers, sodium deoxycholate, sodium caprate and dipotassium glycyrrhizinate, was performed on Caco-2 cell monolayers.

The cytotoxicities of sodium deoxycholate (0.02–0.1% w/v), sodium caprate (0.1–0.5% w/v) and dipotassium glycyrrhizinate (0.5–2% w/v) were evaluated by the trypan blue-exclusion test, the protein-release test, the neutral-red assay, the DNA-propidium iodide staining test and the test for recovery of transepithelial electrical resistance (TEER) up to 24 h after treatment with each enhancer. Sodium dodecyl sulphate (SDS; 0.1% w/v), a potent surfactant, was used as positive control. SDS at this level was significantly cytotoxic whereas dipotassium glycyrrhizinate was not cytotoxic in any tests. Results from the trypan blue-exclusion and protein-release tests showed that high concentrations of sodium caprate (0.5% w/v) and sodium deoxycholate (0.1% w/v) were significantly cytotoxic to the plasma membrane. The neutral-red assay, an indicator of damage to lysosomal membranes, revealed that 0.5% (w/v) sodium caprate had no effect whereas the uptake of neutral red was slightly increased by treatment with 0.1% (w/v) sodium deoxycholate, implying that the compound had cell-growth-enhancing activity. Nuclear-membrane damage, as evaluated by the DNA-propidium iodide staining test, was severe in cell monolayers treated with 0.5% (w/v) sodium caprate compared with that induced by 0.1% (w/v) sodium deoxycholate. In the TEER recovery test, TEER failed to recover 24 h after treatment with 0.5% (w/v) sodium caprate and 0.1% (w/v) SDS, but recovered after treatment with 0.1% (w/v) sodium deoxycholate. The recovery of TEER might be related to nuclear membrane damage and cell-growth-enhancing activity.

These results indicate that of the three classes of enhancer, dipotassium glycyrrhizinate was not cytotoxic and that high concentrations of sodium caprate and sodium deoxycholate could damage plasma and nuclear membranes.
Abstract
Authors: Laight D W , Kaw A V , Carrier M J , Änggård E E
Published: April 2011

Nitric oxide (NO)-mediated vasodilation induced by hyperinsulinaemia might involve an indirect action which promotes agonist-stimulated endothelial function. Our aim was to attempt to demonstrate such modulation of endothelium-dependent vasodilation by insulin in the rat isolated aorta.

We found that vasodilation in response to acetylcholine, but not to adenosine diphosphate (ADP), histamine or the calcium ionophore A23187, was modestly enhanced after 20-min pretreatment with human insulin (100 nM) whereas endothelium-independent responses to the NO donor sodium nitroprusside were not significantly affected.

Human insulin thus has the acute pharmacological action of selectively enhancing muscarinic receptor-mediated endothelial function in rat aortic vascular smooth muscle in-vitro.