bluuebunny/crossref_metadata_2025 huggingface dataset:
In-vitro Bioadhesion of a Buccal, Miconazole Slow-release Tablet
Authors: Bouckaert Stefan , Remon Jean-Paul
Published: April 2011

The bioadhesive characteristics of thermally modified starch/polyacrylic acid (PAA) tablets, containing miconazole nitrate, were determined. The detachment force and work of adhesion were significantly affected by the ratio of drum-dried waxy maize starch and PAA. Pure PAA showed the highest detachment force and work of adhesion while the lowest force and work of adhesion were observed for pure starch. There was a pronounced effect of molecular weight of PAA on the bioadhesive characteristics. Miconazole nitrate did not influence bioadhesion up to a concentration of 30%. The influence of additives was negligible and fluctuations of pH did not influence the bioadhesive strength of the tablet.
Granisetron and Ondansetron: Effects on the Ileal Brake Mechanism in the Rat
Authors: Brown N J , Horton A , Rumsey R D E , Read N W
Published: April 2011

Studies were carried out on 20 male adult rats to investigate how the action of the selective 5-HT3-receptor antagonists, granisetron and ondansetron, influence gastrointestinal transit under control conditions and when stomach-to-caecum transit was delayed by ileal infusion of lipid. Stomach-to-caecum transit time (SCTT) was measured using environmental hydrogen analysis. Subcutaneous administration of granisetron (BRL 43694,40, 80 or 150 μg kg−1) significantly delayed the passage of the head of the baked bean meal through the stomach and the small intestine under control conditions (P < 0·05). Similarly, subcutaneous administration of ondansetron (GR 38032F, 80 or 150 μg kg−1) delayed control SCTT of the head of the meal but this did not reach statistical significance. In contrast, granisetron significantly reversed the delay in SCTT induced by ileal infusion of lipid at 40 (P < 0·001), 80 (P < 0·01) and 150 μg kg−1 (P < 0·05). Ondansetron also reversed the lipid-induced delay at 40 (P < 0·01), 80 (P < 0·001) and 150 μg kg−1 (P < 0·001). These apparently conflicting results may be rationalized by postulating the presence of 5-HT3 receptors on afferent nerves which, when inhibited by the specific antagonists, initiate reflexes that both accelerate and delay transit.
Inhibitory Effect of NZ-105, a 1,4-Dihydropyridine Derivative, on Cyclic Nucloeotide Phosphodiesterase Activity
Authors: Yamashita Toru , Masuda Yukinori , Sakai Toshinori , Tanaka Sakuya , Kasuya Yutaka
Published: April 2011

The effects of NZ-105, a 1,4-dihydropyridine calcium antagonist, on the intracellular cyclic nucleotide system were investigated in-vitro. In rabbit isolated aorta, both NZ-105 (1 and 10 μm) and nicardipine significantly and in a concentration-dependent manner increased intracellular cyclic AMP and cyclic GMP content. NZ-105 inhibited bovine cardiac phosphodiesterase activity (Ki 30 μm) by competitive antagonism. The concentration ranges for inhibition were consistent with the range of increases in cyclic nucleotides.
Effect of Nifedipine on Calcium Status and Chemiluminescence Response of Phagocytes During Plasmodium berghei Infection in Mice
Authors: Kalra A , Dubey M L , Ganguly N K , Mahajan R C
Published: April 2011

The macrophages and neutrophils from nifedipine-treated mice, both Plasmodium berghei-infected and uninfected, showed suppressed capacity to generate oxygen free radicals as compared with untreated controls. Nifedipine treatment did not affect resting state free calcium levels in these cells. But the rise in intracellular calcium levels of macrophages and neutrophils following P. berghei infection was significantly less (P < 0·05) in nifedipine-treated mice as compared with untreated groups at various parasitaemia levels. Probably this reflects a more potent effect of nifedipine on these cells in the depolarized state. Similarly, the rise in intracellular calcium levels of these cells following formyl-Met-Leu-Phe (fMLP) stimulation was also significantly less in nifedipine-treated groups than in untreated controls at different parasitaemia levels. A positive correlation between this fMLP-stimulated rise in calcium levels and the chemiluminescence response of macrophages and neutrophils was observed in nifedipine-treated and untreated groups at various parasitaemia levels. Thus the respiratory-burst responses of these cells during P. berghei infection depend on the calcium homeostasis in the cells. The disturbances of the calcium-regulating mechanisms by nifedipine treatment resulted in subnormal phagocytic cell responses which lead to more severe and rapidly fatal P. berghei infection in these animals.
Conversion of flosequinan to the sulphone metabolite in subcellular fractions of human liver, in-vitro
Authors: Kamali F , Edwards C
Published: April 2011

Flosequinan was metabolized in a NADPH-dependent reaction, by S-oxidation to its principal metabolite, the sulphone. Most of the sulphone metabolite was formed within 20 min and reached a plateau by 60 min, following incubations of flosequinan (31, 61 or 122 μm) with the microsomal fraction. Flosequinan was metabolized mainly by the microsomal fraction. The S-oxidation of flosequinan in incubations containing mitochondrial and cytosolic fractions was 13 and 5%, respectively, of that detected in the microsomal fraction. The route of metabolism of flosequinan in-vitro correlates closely with that previously observed in-vivo. This model could be useful for studying the potential effects of other drugs on flosequinan metabolism in-vitro.
Intragastric Distribution of Ion-exchange Resins: a Drug Delivery System for the Topical Treatment of the Gastric Mucosa
Authors: Burton S , Washington N , Steele R J C , Musson R , Feely L
Published: April 2011

Previous studies by this group on freeze-dried oral dosage forms containing finely-divided ion-exchange resins revealed prolonged gastric residence and uniform distribution within the stomach. The present study was carried out to ascertain whether this was due to freeze-drying, properties of the radiolabeled ionic exchange resin, or the small dosing volume used. 99mTc-labelled cholestyramine resin was administered in two dosage forms, a freeze-dried tablet which dissolved in the oral cavity (orally dissolving tablet; ODT) and a 1.5 mL aqueous suspension. Two resin particle sizes (20–40 and 90–125 μm) were studied. Oesophageal transit and intragastric distribution and residence were followed by gamma scintigraphy. In a second study, in six subjects, gastric emptying of the water-soluble fraction of the ODT and 1.5 mL of water, was measured using 99mTc diethylenetriaminepentaacetic acid.

Oesophageal transit of a water-soluble marker and resin in suspension was rapid, but the transit of the resin in the ODTs was significantly prolonged. Regardless of particle size or dosage form, the resin was evenly distributed throughout the stomach with 20–25% remaining for 5.5 h. In contrast, the water-soluble marker cleared from the stomach rapidly from both dosage forms.

We suggest that oral dose forms containing finely-divided ion-exchange resins may form a useful system for topical treatment of the gastric mucosa, for example in targeting to Helicobacter pylori infection.
Aggravating Process Induced by Indomethacin on Chronic Gastric Lesion in Rat. Role of Polymorphonuclear Leucocytes
Authors: Martin Maria José , Motilva Virginia , Luque Maria Isabel , De La Lastra Catalina Alarcon
Published: April 2011

The present study examines the indomethacin-provoked aggravation of chronic ulceration induced by acetic acid in rats. The drug was administered in a single dose, 7 and 14 days after provocation of ulceration. The changes induced by indomethacin in other groups of animals that had been treated for 7 and 14 days with hydroxyurea (which provokes a marked leucopenia) were also studied.

The results obtained demonstrate that indomethacin does not significantly modify the macroscopic index of ulceration nor vascular permeability in the majority of the groups tested. Only in the group that received hydroxyurea for 14 days was there an increase in both parameters. Myeloperoxidase activity was assayed and used as an index of leucocyte infiltration in an attempt to relate the increase in this activity with a gastrolesive effect. Application of acetic acid produced a significant increase in this activity 7 days after induction of chronic injury. Administration of hydroxyurea intraperitoneally was associated with a decrease in the severity of chronic ulceration and neutrophil infiltration into the gastric mucosa. This effect was detectable enzymatically and microscopically. The groups that received indomethacin showed an increase in myeloperoxidase activity, although this increase was only significant in the animals treated with hydroxyurea for 7 and 14 days.

The results suggest that the aggravation provoked by indomethacin is greater when the ulcer curing process is more advanced.
Effect of Selective Inhibition of Potassium Channels on Vasorelaxing Response to Cromakalim, Nitroglycerin and Nitric Oxide of Canine Coronary Arteries
Authors: Pataricza Janos , Toth Gabor K , Penke Botond , Hohn Jozsef , Papp Julius Gy
Published: April 2011

A comparative study was performed on the sensitivity of in-vitro vasorelaxation by nitroglycerin and cromakalim to block glibenclamide, a blocker of ATP-sensitive potassium channels, and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channels.

In isolated canine coronary arteries preconstricted with 25 μM prostaglandin F2α, nitroglycerin (0.005–1.8 μM) and cromakalim (0.15–9.6 μM) produced dose-dependent vasodilations. Glibenclamide (30 μM) had no significant effect on relaxation of the dose-response curve to nitroglycerin and almost completely abolished the relaxation by cromakalim, a known opener of ATP-sensitive potassium channels. Iberiotoxin (90 nM) decreased the maximal response to nitroglycerin and had no effect on the vasodilation induced by cromakalim. The effect of iberiotoxin on the vasorelaxing action of nitric oxide, the active metabolite of nitroglycerin, was also examined. In a low potassium chloride (14.4–20.4 mM) medium, as a contractile stimulus, iberiotoxin inhibited relaxations by exogenous nitric oxide (100–200 nM). Enhancement of potassium concentrations to 35.4–40.4 mM significantly decreased relaxation by nitric oxide and under these conditions the inhibitory action of iberiotoxin disappeared.

The present study demonstrated that in canine coronary arteries, the functional role of two potassium channels can be separated by pharmacological means. Nitroglycerin-induced vasorelaxation may be mediated, at least in part, by its enzymatic breakdown product, nitric oxide that activates large-conductance calcium-activated potassium channels.
Terpene Penetration Enhancers in Propylene Glycol/water Co-solvent Systems: Effectiveness and Mechanism of Action
Authors: Yamane M A , Williams A C , Barry B W
Published: April 2011

The effects of propylene glycol/water co-solvent systems and terpene penetration enhancers (1,8-cineole, menthone, (+)-limonene and nerolidol) on the absorption rate of the model hydrophilic permeant, 5-fluorouracil, were investigated using excised human skin.

Similar fluxes for 5-fluorouracil were obtained from saturated enhancer-free co-solvent systems. Coapplication of each terpene with the drug, both at saturation, in propylene glycol co-solvent systems increased drug flux significantly. Terpene activity depended on the propylene glycol content in the vehicles. Maximum fluxes were obtained from formulations containing the terpenes in 80% propylene glycol systems (highest concentration used), which when normalized to the flux from the pure vehicles yielded enhancement ratios of about 24, 21, 4 and 18, with 1,8-cineole, menthone, (+)-limonene and nerolidol, respectively. Combining the permeation studies with differential scanning calorimetry (DSC) and partitioning experiments revealed that increased lipid disruption is probably an important mechanism involved in the enhancing ability of formulations containing 1,8-cineole, menthone and nerolidol. This was clearly demonstrated by applying thermodynamic principles to interpret DSC results.

This approach has indicated that these terpenes are probably able to disrupt stratum corneum lipids at physiological temperature as manifested by reductions in the entropy changes associated with the lipid-related transitions, particularly T2, the first major lipid transition. Additionally, increased drug partitioning contributed to the effect of the high propylene glycol content formulations. (+)-Limonene, as interpreted from DSC results, produced a freezing point-depression effect on stratum corneum lipids, suggesting little interaction with lipids at skin temperature; its small enhancement effect may involve phase separation of the oil in stratum corneum lipids.

Terpenes in co-solvent systems such as propylene glycol/water at appropriate propylene glycol content might thus be useful vehicles for the delivery of drugs from topical formulations.
Simultaneous Comparison of Nicotinic Receptor Antagonists on Three Nicotinic Acetylcholine Receptors
Authors: Kerr K P , Stevenson J E , Mitchelson F
Published: April 2011

The relative potencies of several nicotinic cholinoceptor antagonists in producing tetanic fade and reduction of striated muscle contraction were investigated in the isolated guinea-pig oesophagus as well as the guinea-pig and rat phrenic nerve-diaphragm preparations. Contractile smooth muscle responses to vagal stimulation, which involves ganglionic activation, were also measured simultaneously with striated muscle responses in the oesophagus.

The relative potency for inhibiting the response of oesophageal smooth muscle to vagal stimulation (20 Hz) was trimetaphan > mecamylamine > hexamethonium > tubocurarine > pancuronium. For oesophageal striated muscle, production of tetanic fade at 100 Hz and reduction in peak tetanic tension at 20 or 100 Hz showed a similar relative potency; pancuronium > tubocurarine > mecamylamine > trimetaphan > hexamethonium and similar results were obtained in the guinea-pig diaphragm for the antagonists investigated (pancuronium, tubocurarine and mecamylamine). In the rat phrenic nerve-diaphragm preparation, production of tetanic fade at 50 Hz and reduction in twitch or tetanic tension all showed the relative potency; tubocurarine > pancuronium > mecamylamine > trimetaphan > hexamethonium.

These findings indicate differences in the nicotinic cholinoceptor subtypes involved in vagal ganglionic responses and those in tetanic fade.
The Effects of Hepatic Microsomal Enzyme Inducers on the Pharmacokinetics of Ouabain after Portal and Systemic Administration to Rats
Authors: Thompson Thomas N , Klaassen Curtis D
Published: April 2011

The microsomal enzyme inducers 3-methylcholanthrene, phenobarbitone and pregnenolone-16α-carbonitrile (PCN) are known to affect other aspects of hepato-biliary disposition in addition to metabolism. This study was designed to determine if presystemic elimination of the non-metabolized xenobiotic ouabain could be altered by these inducers.

Male Sprague-Dawley rats were pretreated with inducers or saline for four days. A day later, ouabain (0.5 mg kg−1) was administered into either the ileocolic vein (portal administration) or the femoral vein (systemic administration). Blood and bile samples were collected for up to 90 min after ouabain administration. Biliary excretion rate and cumulative biliary excretion of ouabain were increased by pretreatment with PCN (75 mg kg−1 day−1) relative to controls. Phenobarbitone pretreatment (75 mg kg−1 day−1) also increased these parameters, but to a lesser extent than PCN. In contrast, 3-methylcholanthrene pretreatment (20 mg kg−1 day−1) had no effect on biliary excretion. Plasma concentrations of ouabain were much lower after PCN pretreatment relative to controls, whereas neither phenobarbitone nor 3-methylcholanthrene had any effect. Similarly, clearance (both biliary and total) and volume of distribution were increased by PCN, but not by phenobarbitone or 3-methylcholanthrene pretreatment. Interestingly, the magnitude of biliary and plasma effects induced by PCN appeared to be comparable whether ouabain was administered portally or systemically.

Pretreatment of rats with PCN, but not phenobarbitone or 3-methylcholanthrene was shown to increase total clearance of ouabain, mainly via an increase in biliary clearance. Furthermore, because the enhanced clearance occurs after systemic as well as after portal administration of ouabain, a significant change in hepatic presystemic elimination was not detected.
Penetration of β-Blockers through Ocular Membranes in A1bino Rabbits
Authors: Sasaki Hitoshi , Igarashi Yoshiaki , Nagano Toshiaki , Yamamura Kenzo , Nishida Koyo , Nakamura Junzo
Published: April 2011

The purpose of this study was to investigate the barrier properties of ocular membranes for controlling the extent and pathway of ocular absorption of instilled β-blockers.

The penetration of β-blockers was measured across the isolated corneal, conjunctival and scleral membranes of the albino rabbit using a two-chamber glass diffusion cell. β-Blockers tested were atenolol, carteolol, tilisolol, timolol and befunolol.

Corneal penetration of befunolol was much higher than that of atenolol. Scraping the epithelium increased corneal penetration of β-blockers. Conjunctival membranes showed higher permeability than corneal and scleral membranes. The penetration parameters were estimated according to Fick's equation. The corneal permeability coefficient showed an apparent linear relationship with penetrant lipophilicity. The lipophilic character of the corneal barrier was determined by the partition coefficient of drug to corneal surface, not by the diffusion coefficient. Conjunctival and scleral permeability coefficients were not determined by the lipophilicity of β-blockers.

These results indicate that the conjunctiva, sclera and cornea of the rabbit eye are sufficiently different in permeation character to control the extent and pathway for ocular absorption.
Absorption of Isosorbide Dinitrate after Administration as Spray, Ointment and Microemulsion Patch. An In-vitro Study Using the Isolated Perfused Bovine Udder
Authors: Kietzmann M , Wenzel B , Löscher W , Lubach D , Müller B W , Blume H
Published: April 2011

The isolated perfused bovine udder is an in-vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in-vitro model, the percutaneous absorption and metabolism of isosorbide dinitrate (ISDN) was studied.

The organ was perfused with gassed Tyrode solution for up to 6 h. A region of udder skin was treated topically with 60 mg ISDN as a spray, 60 mg ISDN as an ointment and with 120mg ISDN as a microemulsion patch of 30 cm2. Spray and ointment were applied onto a skin region of 400 cm2. The concentrations of ISDN and its metabolites isosorbide-2-mononitrate and isosorbide-5-mononitrate were measured in perfusate fractions by capillary column gas-liquid chromatography with electron capture detection.

Following topical administration of the different formulations, ISDN as well as its metabolites were detected in the perfusate fractions, thus demonstrating that ISDN is metabolized by the udder skin in-vitro. A maximum amount of ISDN was absorbed after administration as a spray followed by ointment and microemulsion (5, 2·5 and 1·8 μmol total organic nitrate, respectively). In contrast, the ISDN flux per cm2 skin was significantly higher after administration of the microemulsion (64·4 pmol cm−2 min−1 for the microemulsion compared with 21·9 and 10·2 pmol cm−2 min−1 for spray and ointment).
Sapintoxin A and Phorbol 12, 13-Dibutyrate: Two Phorbol Derivatives with Contrasting Effects on Rat Blood Vessel Permeability In-vitro
Authors: Northover A M , Northover B J , Ryves W J , Evans F J
Published: April 2011

Rat isolated small intestine and mesentery were perfused with a gelatin-containing physiological salt solution, and microvascular permeability in the villi was assessed using colloidal carbon as a marker to assess the effect of sapintoxin A in this experimental situation, and to compare it with phorbol 12, 13-dibutyrate.

Sapintoxin A (1, 0·25, 0·1 μm) had no effect on colloidal carbon leakage compared with control values, but significantly increased perfusion pressure. Phorbol 12, 13-dibutyrate (1 μm) significantly increased both colloidal carbon leakage and perfusion pressure. Pretreatment with the protein kinase C inhibitor Ro 31–8220 (1 μm) significantly increased colloidal carbon leakage in the presence of sapintoxin A, but significantly decreased the phorbol 12, 13-dibutyrate-induced leakage of colloidal carbon.

Pretreatment with indomethacin (1 μm) significantly increased colloidal carbon leakage in response to sapintoxin A, but did not affect the response to phorbol 12, 13-dibutyrate. Increases in perfusion pressure caused by sapintoxin A (0·25 μm) and phorbol 12, 13-dibutyrate (1 μm) were reduced by Ro 31–8220, but neither pressor response was affected by indomethacin. Lower concentrations of phorbol 12, 13-dibutyrate (0·25, 0·1 μm) had no effect on colloidal carbon leakage. However, there was a significant increase in perfusion pressure in response to 0·25 μm but not to 0·1 μm phorbol 12, 13-dibutyrate.

When rat mesentery alone was perfused using gelatin-free physiological salt solution, sapintoxin A (1 μm) had no effect on perfusion pressure, whereas phorbol 12, 13-dibutyrate (1 μm) caused a significant increase over a 15-min period, which was completely abolished by pretreatment with Ro 31–8220.

It may be concluded that the permeability-increasing effects of phorbol 12, 13-dibutyrate are dependent on protein kinase C activation.
Further Studies on the Antinociceptive Action of the Hydroalcoholic Extracts from Plants of the Genus, Phyllanthus
Authors: Santos Adair R S , Filho Valdir C , Yunes Rosendo A , Calixto João B
Published: April 2011

The analgesic effects of the hydroalcoholic extracts (HEs) of Phyllanthus urinaria, P. tenellus, P. niruri and P. sellowianus have been investigated in several models of nociception in mice.

The HE of four species of Phyllanthus (1–90 mg kg−1, i.p.) caused a dose-related inhibition of acetic acid-induced abdominal constriction in mice with ID50 values of 5·4, 8·5, 18·2 and 53·0 mg kg−1 and maximal inhibition (%) of 80 ± 2, 67 ± 8, 63 ± 8 and 50 ± 4 for P. urinaria, P. niruri, P. tenellus and P. sellowianus, respectively. In the formalin test, the HE of all Phyllanthus species (0·3–60 mg kg−1, i.p.) caused graded inhibition of both phases of formalin-induced pain, but they were, however, more potent in relation to the second phase of the pain. The ID50 values (mg kg−1) for the first phase were 20·0, 23·0, > 60, and > 60 for the P. urinaria, P. tenellus, P. niruri and P. sellowianus, respectively, and percentages of maximal inhibition were 63 ± 2, 70 ± 2,41 ± 3 and 46 ± 4, respectively. The ID50 values (mg kg−1) for the second phase were 0·71, 4·87, 7·7, 33·0, with maximal inhibition (%) of 91 ± 6, 97 ± 3, 97 ± 3 and 92 ± 6, respectively. Given orally, the HEs of species of Phyllanthus caused a significant antinociceptive profile, but they were about one-tenth to one-twentieth as potent when given intraperitoneally. However, the HEs of Phyllanthus failed to affect formalin-induced paw oedema and did not interfere with the performance of animals in the rota-rod test. Naloxone (5 mg kg−1) completely reversed the analgesic effect caused by morphine (5 mg kg−1), but had no effect against the analgesic effect of the HE of Phyllanthus. Furthermore, the HEs of Phyllanthus in contrast to morphine had no analgesic effect in either tail-flick or hot-plate tests.

Taken together, these findings confirm and extend our previous results and indicate that all studied HE of species of plant belonging to the genus Phyllanthus exhibit potent and long-lasting antinociceptive activity in several models of pain, including the neurogenic algesic component of the formalin test. The mechanism underlying their analgesic profile is presently unknown.
The Binding of Two Dihydropyridines to Isolated and Native Plasma Lipoproteins
Authors: Oravcová Jana , Sojková Dagmar
Published: April 2011

The objectives of this study were to investigate the mechanisms involved in the interaction of two calcium antagonists, isradipine and amlodipine, with isolated lipoprotein fractions in-vitro and to determine the distribution of isradipine among individual plasma lipoproteins ex-vivo in healthy volunteers (n = 8) and in hypercholesterolaemic patients (n = 12).

The total binding affinity of isradipine to isolated low density lipoprotein (LDL) was markedly higher compared with amlodipine; total binding affinity (nKa) of isradipine vs amlodipine was 1·60 ± 0·08 times 107 vs 4·14 ± 0·33 times 106  m-1, respectively. Binding to high density lipoprotein (HDL) was also higher with isradipine, nKa = 1·04 ± 0·04 times 105  m−1, compared with that of amlodipine, nKa = 3·82 ± 0·18 times 104  m−1. The distribution study ex-vivo demonstrated the different relative affinity of isradipine for the plasma lipoproteins: HDL > LDL > very-low density lipoprotein (VLDL). Isradipine binding correlated linearly with the cholesterol levels in LDL and VLDL; however, binding to HDL did not correlate with the cholesterol level in this fraction. There was no significant competitive binding effect of cyclosporin A (1–5 μgmL−1) on isradipine binding to individual lipoprotein fractions.

It is likely that, in addition to the structure of surface apoproteins, the factors determining the interaction of calcium antagonists with plasma lipoproteins also include the plasma level of each lipoprotein fraction as well as the lipophilicity of the drug.
Rat Liver Cytochrome P450-mediated Metabolic Activation of Methoxsalen and Structurally Related Compounds and its Relation to Enzyme Inhibition
Authors: Wilkinson David J , Fry Jeffrey R
Published: April 2011

The metabolic activation and enzyme inhibition characteristics of methoxsalen were investigated in rat liver microsomes obtained from untreated animals and those treated with a number of prototypic inducers of cytochrome P450.

Glutathione depletion assays have been carried out which show reactive metabolite generation to be markedly increased following phenobarbitone and β-naphthoflavone induction. Moreover, isoniazid induction led to levels of glutathione depletion significantly higher than those seen with other forms of induction, suggesting an important role for the cytochrome P4502E1 isozyme in the metabolic activation process.

Methoxsalen was shown to be an extremely potent inhibitor of 7-ethoxycoumarin-O-de-ethylase activity, with inhibition constants of the order of μm with microsomes obtained from untreated, phenobarbitone- and β-aphthoflavone-induced animals. In contrast, constants obtained with microsomes obtained from isoniazid-induced animals were found to be markedly higher.

Comparisons of the inhibition of 7-ethoxy and 7-pentoxyresorufin-O-dealkylase activities by methoxsalen and a number of structurally-related compounds have shown that a complete tricyclic ring system and an unsaturated 4′,5′-bond are structural prerequisites in the formation of reactive metabolites which inhibit cytochrome P450. These data implicate the furan ring system as the source of these metabolites and rule out the involvement of the pyrone ring system in the inhibition process.
Comparative Convulsant Potencies of Two Carbapenem Derivatives in C57 and DBA/2 Mice
Authors: De Sarro A , Imperatore C , Mastroeni P , De Sarro G
Published: April 2011

The behavioural and convulsant effects of imipenem and meropenem were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizure, and in C57 mice, a strain not prone to seizure.

DBA/2 mice were more susceptible than C57 mice to seizures induced by imipenem-cilastatin or meropenem. Imipenem was also 1·9 times more potent than meropenem in inducing clonus in DBA/2 mice.

To investigate the possibility that the seízure-inducing activity of imipenem might be due to a probenecid-like effect of cilastatin, animals were treated with imipenem alone.

No significant differences were observed between imipenem-cilastatin and imipenem-treated animals. Thus, it is reasonable to exclude a probenecid-like effect of cilastatin. Although the main mechanism for seizure-like activity of imipenem cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of imipenem from the CNS may be postulated. Cilastatin did not induce seizures. In addition, meropenem, a compound structurally related to imipenem, showed weak or no convulsant effects.
Contributions of β-Adrenoceptor Subtypes to Responses to Isoprenaline in Rat Isolated Distal Colon
Authors: McKean Jennifer , MacDonald Allan
Published: April 2011

The effects of the non-selective β-adrenoceptor antagonist propranolol and the β1 and β2-adrenoceptor-selective antagonists, respectively CGP 20712A (((±)-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanol hydrochloride)) and ICI 118,551 ((erythro(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol-hydrochloride)), on isoprenaline-induced inhibition of methacholine contractions in rat distal colon were investigated to determine the contributions of β-adrenoceptor subtypes to relaxation of smooth muscle.

Longitudinal segments of rat distal colon were suspended in Krebs solution at 37°C for isometric recording. The Krebs solution contained EDTA (30 μm), ascorbic acid (30 μm) and prazosin (0·1 μm) and was gassed with 95% O2−5% CO2. Isoprenaline produced a concentration-dependent inhibition of methacholine-induced contractions. Propranolol produced a small (4–6-fold) significant shift of the isoprenaline concentration-response curve at 0·003–0·01 μm. Larger shifts were produced by 0·3 μm (13-fold) and 1 μm (20-fold). CGP 20712A produced a small (3–5-fold) significant shift at 0·03–1 μm. ICI 118,551 produced small non-significant shifts (2–3-fold) at 0·03–1 μm. A combination of ICI 118,551 (0·3 μm) and CGP 20712A (0·1 μm) produced a 13-fold shift, a significantly greater shift than expected from the individual shifts. The shift produced by the combination of antagonists was slightly less than that produced by 1 μm propranolol (20-fold).

The effects of propranolol appear to be due mainly to a combination of β1 and β2-adrenoceptor blockade, although an additional action of propranolol at β3-adrenoceptors is likely.
Percutaneous Absorption of Indomethacin from Pluronic F127 Gels in Rats
Authors: Miyazaki Shozo , Tobiyama Takeshi , Takada Masahiko , Attwood David
Published: April 2011

Thermally reversible gels of the poly(oxyethylene)-poly(oxypropylene)-(polyoxyethylene) triblock copolymer, Pluronic F127, were evaluated as vehicles for the percutaneous administration of drugs using indomethacin as a model drug.

In-vivo percutaneous absorption studies using a rat model suggest that a 20% w/w aqueous gel of Pluronic F127 may be of practical use as a base for topical administration of the drug. The addition of isopropyl myristate or (+)-limonene to the gel formulation significantly improved percutaneous absorption, particularly when the gel was applied using an occlusive dressing technique.
Usefulness of the Pain-induced Functional Impairment Model to Relate Plasma Levels of Analgesics to Their Efficacy in Rats
Authors: Hoyo-Vadillo Carlos , Pèrez-Urizar José , López-Muñoz Francisco J
Published: April 2011

In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen.

Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered.

The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.
Improving the Oral Bioavailability of Sulpiride by Sodium Oleate in Rabbits
Authors: Naasani Imad , Kohri Naonori , Iseki Ken , Miyazaki Katsumi
Published: April 2011

To improve the limited oral bioavailability of sulpiride, a dosage form containing sodium oleate as an absorption enhancer was developed and evaluated using gastric-emptying-controlled rabbits in a cross-over manner.

In addition to the known properties of sodium oleate with respect to modifying the permeability of biomembranes, it was found to be capable of improving the physicochemical properties of sulpiride toward a higher lipophilicity (by ion-pair association) and a higher solubility (by micellar solubilization). Nonetheless, the incorporation of sodium oleate with sulpiride as a mixture filled in hard gelatin capsules failed to increase intestinal absorption, whereas the use of enteric capsules, instead of the hard gelatin capsules resulted in a significant increase (P < 0·05) in the oral bioavailability.
Development of a Colon Delivery Capsule and the Pharmacological Activity of Recombinant Human Granulocyte Colony-stimulating Factor (rhG-CSF) in Beagle Dogs
Authors: Takaya Tomohiro , Ikeda Chikako , Imagawa Naoya , Niwa Kiyoshi , Takada Kanji
Published: April 2011

A peroral dosage form was examined to deliver recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the colon in beagle dogs. A new gelatin capsule with its inside surface coated with ethylcellulose was prepared for this purpose. RhG-CSF was dissolved with propylene glycol and was filled in the capsule. Several kinds of ethylcellulose-gelatin capsules with an ethylcellulose layer of thickness 46 to 221 mm were used. The capsule was filled with propylene glycol solution containing fluorescein as an absorption marker, castor oil derivative and citric acid. The hardness of the capsule was tested after the gelatin layer was dissolved using a hardness tester and was dependent on the thickness of the ethylcellulose layer of the capsule.

The time, Tmax, at which plasma fluorescein level reaches its maximum following oral administration of ethylcellulose capsules was used as a parameter for the in-vivo disintegration time of the ethylcellulose capsule into the colon. Capsules of thickness 84 mm with a Tmax of 4–6 h were filled with rhG-CSF solution containing fluorescein and were administered to dogs. After administration, blood samples were collected for 96 h and the blood total leucocyte (BTL) counts were measured as a pharmacological index of rhG-CSF.

The maximum BTL count appeared at 10 h then gradually decreased and returned to its normal level at 48 h. These results suggest the usefulness of ethylcellulose capsules for the delivery of rhG-CSF to the colon and the possibility of a new oral rhG-CSF dosage form has been elucidated.
Comparison of Body Distribution of Poly(vinyl alcohol) with Other Water-soluble Polymers after Intravenous Administration
Authors: Yamaoka Tetsuji , Tabata Yasuhiko , Ikada Yoshito
Published: April 2011

The body distribution of poly(vinyl alcohol) (PVA) with molecular weights (MW) from 14800 to 434000 Da was investigated after intravenous administration and compared with that of other water-soluble polymers such as poly(ethylene glycol) (PEG), gelatin, dextran, and pullulan.

The half-life of PVA in the circulation was prolonged from 90 min (MW 14800 Da) to 23 h (MW 434000 Da), similar to that of PEG which had a half-life of 30 min (MW 6000) and 20 h (MW 170000). However, the half-life of PVA was much longer than that of other polymers when compared at a similar molecular weight. PVA was located in most organs but with very small accumulation. An insignificant interaction of PVA with cell components, such as macrophages and blood cells, was observed. Similar to PEG, the excretion rate of PVA at the glomeruli was rapidly reduced around 30000 Da, as the molecular weight increased.

These results indicate that the half-life of intravenously injected PVA in the blood was mainly determined by the permeation characteristics of the kidney.
Role of Acid Back-diffusion in the Formation of Mucosal Ulceration and Its Treatment with Drugs in Diabetic Rats
Authors: Hung Chen-Road , Huang Eng-Yen
Published: April 2011

We have studied the role of acid back-diffusion in the formation of gastric mucosal ulceration and its treatment with several drugs in streptozotocin-induced diabetic rats. After vagotomy, the stomach of 1–8 week-old diabetic rats and age-matched control rats were irrigated with acid solutions of graded concentrations (50–150 mm HCl) for 1 or 3 h.

A marked increase in acid back-diffusion and in haemorrhagic ulceration was found in diabetic rats. The extent of acid back-diffusion and the severity of mucosal ulceration were dependent on the concentration and the time of contact of acid solutions with the gastric mucosa. A high correlation (r = −0·9227) between acid back-diffusion and mucosal ulceration was found in 3-h acid-irrigated diabetic rats.

In the 2-week diabetic rat, intragastric cimetidine (300 mg kg−1) or NaHCO3 (52 mg kg−1) significantly (P < 0·05) reduced both acid back-diffusion and haemorrhagic ulcer formation, while atropine (1·0 mg kg−1) or bupivacaine (0·5%, 0·4 mL/rat) was ineffective. High blood glucose levels in diabetic rats were not influenced by these agents. Acid back-diffusion and ulceration in the diabetic rat were markedly reduced by daily administration but not single injection of insulin (50 units kg−1, s.c.).

Taken together, in the early stage of diabetes development, chronic insulin deficiency rather than nerve degeneration or hyperglycaemia may be responsible for the disruption of mucosal barriers. It is concluded that acid back-diffusion played an important role in the formation of acute haemorrhagic ulceration that can be inhibited by intragastric cimetidine, NaHCO3 or daily injection of insulin.
Fluid and Protein Secretion by the Submandibular Glands of Weanling Rats in Response to Cholinergic and Peptidergic Agonists at Various Doses
Authors: Baba Atsuko , Taniguchi Kunihisa , Motokawa Wataru , Ishibashi Kazunari , Okina Atsuhito , Abe Kimio
Published: April 2011

Fluid and protein secretion by the submandibular glands of 25-day-old rats were examined and compared in response to three cholinergic and four peptidergic sialogogues at various doses.

All cholinergic and peptidergic agonists used were potent sialogogues for the submandibular glands of the weanling rats over the wide range of doses used. The cholinergic agonists, bethanechol and methacholine and the peptidergic agonists, substance P, substance PTyr8 and eledoisin-related peptide used intravenously, acted similarly to each other on the submandibular glands of the rats, late in the natural weaning period, but carbachol and physalaemin had slightly different effects. Of the peptidergic agonists, physalaemin was the most potent sialogogue among four tachykinins tested at the low dose. The types of protein secreted by the submandibular glands of the weanling rats in response to all sialogogues used here were typical of the β-type.

These results indicate that all agonists used could mainly stimulate the acinar cells of the submandibular glands of the weanling rats which have already fully developed functionally at this time.
Enthalpy and Entropy Contributions to the Solubility of Sulphamethoxypyridazine in Solvent Mixtures Showing Two Solubility Maxima
Authors: Bustamante P , Escalera B
Published: April 2011

The solubility of sulphamethoxypyridazine was measured at several temperatures in mixtures of water: ethanol and ethanol: ethyl acetate. Sulphamethoxypyridazine was chosen as a model drug to compare the solvation effects of proton donor-proton acceptor (water and ethanol) and proton acceptor (ethyl acetate) solvents and mixtures of these solvents because this drug contains functional groups capable of Lewis acid-base interaction.

A plot of the mole fraction solubility against the solubility parameter (δ1) of these solvent mixtures showed two solubility maxima, one at δ1 = 30·87 MPa1/2 (20:80 v/v water: ethanol) and another at δ1 = 20·88 MPa1/2 (30:70 v/v ethanol: ethyl acetate) at all the temperatures under study. The enthalpies and entropies of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol to water:ethanol and ethanol:ethyl acetate mixtures were calculated to compare solvation characteristics of the solvent mixtures toward the drug. As ethanol is added to water, the entropy increases and the structure of the solvent mixture became less ordered, favouring the interaction of the drug with the solvent mixture. On the other hand, in the case of the ethanol: ethyl acetate mixture, solubility is favoured by the more negative enthalpy values. This way, the same result, i.e. a solubility maximum, is obtained by different routes.

In the ethanol: water mixtures, the dissolution process is entropy-controlled while enthalpy is the driving force in the case of ethanol: ethyl acetate mixtures. The two solvent systems show enthalpy-entropy compensation. Water deviates from the linear relationship due possibly to its hydrophobic effect.
5-HT3 Receptor-independent Inhibition of the Depolarization-induced 86Rb Efflux from Human Neuroblastoma Cells, TE671, by Ondansetron
Authors: Toral Joyce , Hu William , Critchett Donald , Solomon Andrew J , Barrett James E , Sokol Patricia T , Ziai M Reza
Published: April 2011

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells.

This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 (M), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205–930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron.

A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(lH)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.
In-vitro Bronchorelaxing Effects of Novel Nitric Oxide Donors GEA 3268 and GEA 5145 in Guinea-pigs and Rats
Authors: Vaali Kirsi , Li Liang , Redemann Beatrix , Paakkari Ilari , Vapaatalo Heikki
Published: April 2011

Endogenously released nitric oxide (NO) in airways might contribute to physiological bronchodilation; induced production of NO might play a role in the pathogenesis of asthma, although it could also be a compensatory mechanism to other factors that cause bronchoconstriction or inflammation. To investigate the efficacy of NO donors on bronchial tone, the bronchorelaxing efficacies of NO donors, new experimental GEA compounds 3268 and 5145 (oxatriazole sulphonylamides) were compared with those of sodium nitroprusside and SIN-1 (3-morpholinosydnonimine) and to the standard β2-adrenergic agonist, salbutamol, in bronchi of guinea-pigs and rats in-vitro. Their relaxing effects were also studied in rat mesentery arteries to compare the selectivity for airways. The capacity of the NO donors to produce nitrites and nitrates was assayed by the Griess reaction.

The novel NO donors GEA 3268 and GEA 5145 were more potent bronchorelaxing agents than the old NO donors sodium nitroprusside and SIN-1. In guinea-pig bronchi, however, salbutamol was most potent. In rat bronchi the GEA compounds induced the strongest relaxation effect when compared with the old NO donors or with salbutamol. The airway selectivity of the drugs studied decreased in the order of salbutamol, SIN-1, GEA 5145, GEA 3268, sodium nitroprusside. The nitrites and nitrates produced spontaneously did not correlate with the efficacy of the relaxants

The results obtained suggest that NO is only partly responsible for the relaxation and the potency is dependent on the animal species and constricting agents used.
Pharmacological Activity of DC−015, a Novel Potent and Selective α1-Adrenoceptor Antagonist
Authors: Yen M H , Sheu J R , Peng I H , Lee Y M , Chern J W
Published: April 2011

The pharmacological activity of 3−((4−(2−methoxyphenyl)piperazin−1−yl)methyl)−2,3−dihydroimidazo(1,2−c)quinazolin−5(6H)-one (DC−015), a newly synthesized quinazoline derivative, was determined in rat isolated thoracic aorta and pressor responses were determined in spontaneously hypertensive rats (SHR).

Experimental results indicated that DC−015 is an α1-adrenoceptor-blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasocontraction (pA2 = 10ṁ54 ± 0ṁ55). These effects still persisted in denuded aorta. It was as potent as prazosin (pA2 = 10ṁ04 ± 0ṁ63). At higher concentrations (1ṁ0 μM), DC−015 also expressed 5−hydroxytryptamine (5−HT) receptor competitive antagonism, but this 5−HT blocking effect was not found in the prazosin-administration group. [3H]Inositol monophosphate formation stimulated by phenylephrine (30 μM) in rat thoracic aorta was diminished by DC−015 (3 and 10 nM) and prazosin (10 nM); whereas the cAMP content of rat thoracic aorta was not altered by DC−015 and prazosin. Furthermore, intravenous administration of DC−015 and prazosin (both at 0ṁ01, 0ṁ05 and 0ṁ1 mg kg11) induced a dose-dependent reduction of mean arterial pressure which reached a maximal effect at 5 min after injection and persisted over 2 h in SHR. A higher dose of DC−015 (0ṁ1 mg kg−1, i.v.) did not cause any significant changes in heart rate, whereas, the same dose of prazosin (0ṁ1 mg kg−1, i.v.) produced a decrease which seems to parallel the time course of the hypotensive response.

We can conclude that the DC−015 is a potent, highly selective α1-adrenoceptor antagonist in vascular smooth muscle.
Structure-activity Relationships of Some Novel Coronary Dilator Derivatives of Palmitoyl Carnitine in the Rat Isolated Heart
Authors: Reeves K A , Dewar G H , Rad-Niknam M , Woodward B
Published: April 2011

The structure-activity relationships of some novel coronary dilator derivatives of palmitoyl carnitine in the rat isolated perfused heart are described.

It has been shown previously that esterification of palmitoyl carnitine changes the activity of the compound from a coronary constrictor to a coronary dilator. In this study, it was found that the ester group is not a necessary requirement for coronary dilator activity, but only the absence of the negatively charged carboxylic acid group of palmitoyl carnitine, as compounds containing an ethyl group in place of the ester group were also active coronary dilators. Furthermore, substituting the methyl groups attached to the nitrogen atom of the molecule profoundly altered coronary dilator activity. A quaternary ammonium group was a necessary requirement for potent coronary dilator activity.