bluuebunny/crossref_metadata_2025 huggingface dataset:
Pertechnetate release from a water/oil microemulsion and an aqueous solution after subcutaneous injection in rabbits
Authors: Bellâ M , Colangelo D , Gasco M R , Maranetto F , Morel S , Podio V , Turco G L , Viano I
Published: April 2011

A water-oil microemulsion and an aqueous solution, both carrying pertechnetate, were injected subcutaneously in rabbits; release was observed by imaging the administration sites with a gamma-camera. Disappearance from the injection site of pertechnetate in aqueous solution was about ten times faster than that of pertechnetate in a microemulsion.
Cardiac response to autonomic drugs in atria of diabetic mouse
Authors: Wong Kai K
Published: April 2011

Comparisons of chronotropic effects of sympathomimetic and parasympathomimetic agents were made in isolated atria from alloxan-induced diabetic and age-matched control mice. In atria from mice rendered diabetic for three months, the cardiac response to bethanechol was potentiated compared with that of the age-matched control atria. However, the cardiac responses of atria from alloxan-treated mice to noradrenaline, 3-isobutyl-1-methylxanthine and 1,1-dimethyl-4-phenyl piperazinium iodide were similar to those of the controls.
The effect of low temperature on the enzyme activities and the level of SH groups in benign gastric ulcer and gastric carcinoma
Authors: Rzymowska J
Published: April 2011

Homogenates of human benign gastric ulcers and gastric carcinomas were stored at a low temperature (4°C). The activities of l-lactate dehydrogenase (LDH), malic dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH), glutathione reductase (GR) and the concentrations of SH-containing compounds showed changes. Increased activities of LDH, MDH, G6PDH and GR occurred in the gastric carcinomas stored at 4°C compared with controls at 37°C. In contrast, the activities of G6PDH and GR decreased in the tissues of benign gastric ulcers. On incubation at 4°C the SH-containing compounds incorporated into protein molecules, SH groups binding with protein and non-protein SH groups decreased in both the benign and malignant tissues.
Evaluation of free radical production in an ischaemia-reperfusion model in the rabbit using a tourniquet
Authors: Chopineau J , Sommier M F , Sautou V
Published: April 2011

Use of a tourniquet on a limb to stem blood flow is frequent in surgery. However, this results in an ischaemia-reperfusion effect that causes damage through the production of free radicals. The aim of this work was to evaluate this production of free radicals in an ischaemia-reperfusion model in the rabbit after placement of a tourniquet. Plasma lipoperoxides were measured by high-performance liquid chromatography using the malondialdehyde assay method. We found significant (P < 0·01) production of free radicals 1 min after release of the tourniquet compared with controls; no variation in levels of free radicals was observed during the ischaemia phase.
Rheological Behaviour of Saturated Polyglycolysed Glycerides
Authors: Bourret E , Ratsimbazafy V , Maury L , Brossard C
Published: April 2011

Seven saturated polyglycolysed glycerides (Gelucires) of melting points varying from 42 to 53°C and hydrophilic-lipophilic balance values from 2 to 14 were selected. Their rheological behaviour was determined by adjustment of the flow curves to the Ostwald power-law and by statistical assessment of the flow index. The flow of Gelucires was slightly shear thickening. This shear thickening rose when the temperature and the lipophilic specificity of the Gelucire increased. This behaviour accounted for a reorganization of the particles under the shear which became easier when the temperature increased and when the degree of condensation of the polyethylene glycol chains decreased with lipophilicity of the Gelucires.
The Power-consumption-controlled Extruder: A Tool for Pellet Production
Authors: Kleinebudde P , Sølvberg A J , Lindner H
Published: April 2011

Based on the assumption that there is a link between power consumption of an extruder and pellet properties, a control circuit for power consumption was developed. Powder and granulation liquid are feeded separately into a twin-screw extruder. The power consumption is controlled by varying the pump rate at a given powder-feed rate; consequently each level of power consumption results in a specific water content of the extrudate for a particular formulation. The shape of pellets depends almost entirely on the level of power consumption irrespective of formulation. The size of dry pellets is additionally affected by a shrinking factor which depends on the water content. The power-consumption-controlled extruder is an appropriate tool for the production of pellets. The system is able to adapt the water content for a formulation automatically.
Calcitonin and Insulin in Isobutylcyanoacrylate Nanocapsules: Protection Against Proteases and Effect on Intestinal Absorption in Rats
Authors: Lowe Philip J , Temple Cathy S
Published: April 2011

One of the major limiting steps for the absorption of peptide drugs from the intestine is proteolytic degradation. To slow this degradation, human calcitonin was trapped in polyacrylamide nanoparticles, and human calcitonin and insulin were encapsulated with polyisobutylcyanoacrylate. Human calcitonin trapped in polyacrylamide nanoparticles showed no delayed release characteristics and thus would not provide protection from proteases. Proteolytic degradation of human calcitonin and insulin in polyisobutylcyanoacrylate nanocapsules was slower than the free peptides in solution. The plasma pharmacokinetic profiles were consistent with increased survival time of the peptides in the intestine, with higher plasma concentrations of the peptides in the later time samples compared with the controls. However, the nanocapsules gave no significant overall enhancement of peptide absorption. This led to the conclusion that the nanocapsules released the peptides into the intestinal lumen, with small amounts then being absorbed but the rest largely degraded.
Hepatobiliary Disposition of 3′-Azido-3′-deoxythymidine (AZT) in the Rat: Effect of Phenobarbitone Induction
Authors: Bezek Štefan , Kukan Marián , Bohov Pavol
Published: April 2011

Isolated liver with a recirculating perfusate was used to study 3′-azido-3′-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 μm AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0·42 ± 0·01 (mean ± s.d.) mL min−1/10 g liver. Over the study period of 105 min, 12·7 ± 2·6% of the dose was excreted in bile and of this 95% was recovered as 3′-azido-3′-deoxy-5′-O-β-d-glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5·5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0–105  min) for 3′-amino-3′-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0–250 μm) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane. Rats dosed intraduodenally with [3H]GAZT excreted 5·8 ± 3·3% of the GAZT dose in bile within 4 h after administration. This suggests that enterohepatic recycling is involved in AZT disposition in the rat.
The Recognition of a Diarylimine as a Metabonate Produced During Incubation of N-Benzyl-4-chloroaniline with Hepatic Microsomal Preparations
Authors: Ulgen Chian-Ming Low M , Gorrod J W
Published: April 2011

Evidence is presented for the formation of N-benzylidene-4-chloroaniline as a metabonate during the metabolism of N-benzyl-4-chloroaniline. Control studies suggest that the diarylimine is formed as a chemical artifact from the debenzylation products (benzaldehyde and 4-chloroaniline). This novel observation indicates a possible pathway to amide formation from N-benzylanilines via diarylimines as intermediates.
Pharmacokinetic and Pharmacodynamic Studies of the Histamine H1-Receptor Antagonist Ebastine in Dogs
Authors: Puigdemont Anna , Queralt Mireia , Jansat Josep M , Martinez-Tobed Antonio
Published: April 2011

The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0·01 mL of a 0·2 mg mL−1 histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4·38 ± 1·01 h after 10 mg ebastine and 4·09 ± 0·74 h after 20 mg ebastine; the distribution volume was 3·99 ± 0·88 and 3·65 ± 0·75 L kg−1 after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0·67 ± 0·24 L h−1 kg−1 and after 20 mg ebastine was 0·63 ± 0·17 L h−1 kg−1. The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0·001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3–4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0·17 and 0·22 h−1 after 10 and 20 mg ebastine with a half-life of 4·13 and 3·56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18·9 ± 4.8 ng mL−1 after 10 mg and 18·2 ± 5.7 ng mL−1 after 20 mg ebastine.
Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers
Authors: Uematsu T , Kanamaru M , Nakashima M
Published: April 2011

The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY-5763) were studied to analyse the relationship between plasma concentration and QTc prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6·5 days, and single intravenous doses of 1·0 and 1·5 mg kg−1. The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7·9–9·7 h. The Cmax and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66–68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased biexponentially with a terminal half-life of 7·6–8·3 h and the urinary recovery as unchanged drug amounted to 84–88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QTc interval and concentration of (+)-sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment. This analysis was shown to be effective to adjust the lag of effect behind a rapid change in plasma concentration which occurred in the early distributive phase because there was no evidence that the metabolite made any significant contribution to the effect of (+)-sotalol.
Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats
Authors: Santa Tomofumi , Nishihara Kazuyo , Horie Shigeo , Kotaki Hajime , Sawada Yasufumi , Kawabe Kazuki , Iga Tatsuji
Published: April 2011

Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression.
Effect of Topical Preparation of Mycophenolic Acid on Experimental Allergic Contact Dermatitis of Guinea-pigs Induced by Dinitrofluorobenzene
Authors: Shoji Yoko , Fukumura Tadashi , Kudo Masataka , Yanagawa Akira , Shimada Jingoro , Mizushima Yutaka
Published: April 2011

The effects of a topical preparation of mycophenolic acid on the experimental allergic contact dermatitis induced by dinitrofluorobenzene was investigated. Visual assessment of skin reactions showed significant efficacy of a topical preparation of mycophenolic acid. This efficacy appeared from the early stage and endured up to 3 days. Morphological changes in the epidermis and dermis layers of animals treated with a mycophenolic acid cream were moderate compared with that in animals treated with vehicle only. In particular, hyperkeratosis was strongly suppressed. Since suppression of inflammatory cell infiltration was also observed, this efficacy might reach to the epidermis and dermis layer.
Anti-hypertensive Effect of Oral Controlled-release Microspheres Containing an ACE Inhibitor (Delapril Hydrochloride) in Rats
Authors: Akiyama Yohko , Yoshioka Minoru , Horibe Hidetoshi , Inada Yoshiyuki , Hirai Shinichiro , Kitamori Nobuyuki , Toguchi Hajime
Published: April 2011

An oral controlled-release drug delivery system based on microspheres of polyglycerol esters of fatty acids (PGEFs), was applied to an anti-hypertensive, delapril hydrochloride. The in-vitro release profile was controlled by selecting a PGEF with an appropriate hydrophilic-lipophilic balance value for the matrix. The microspheres from which 80% of the drug was released in 6 h were orally administered to rats. The plasma concentration of the active metabolite was sustained after administration of the microspheres in comparison with administration of a solution. The in-vivo release profile was in good agreement with the in-vitro release profile. When the microspheres were administered, the pharmacological effect of delapril hydrochloride on the angiotensin I-induced pressor response was also sustained showing consistency with the plasma concentration-time curve.
Cyclosporin Increases the CNS Sensitivity to the Hypnotic Effect of Phenobarbitone but not Ethanol in Rats
Authors: Hoffman Amnon , Habib Gustav , Gilhar Dalia , Zohar Hila
Published: April 2011

The purpose of this investigation was to determine whether repetitive administration of cyclosporin affects the pharmacodynamics of phenobarbitone- and ethanol-induced anaesthesia. Sabra male rats received either cyclosporin (50 mg kg−1 day−1, i.m.) for four days, or the same volume of the vehicle. Two hours after the last cyclosporin dose, phenobarbitone or ethanol solutions were infused intravenously at a constant rate until the onset of anaesthesia. Repetitive treatment with cyclosporin increased the CNS sensitivity to the hypnotic action of phenobarbitone. This was evidenced by the lower CSF phenobarbitone concentration, at the onset of the hypnotic effect, in the cyclosporin-treated group vs control values (115 ± 4 vs 93 ± 7 mg L−1, P = 0·01). However, the same pretreatment had no apparent effect on the pharmacodynamics of ethanol-induced sleep. It is suggested that anaesthesiologists must be alert to the possible increase in brain sensitivity when placing cyclosporin patients under anaesthesia with barbiturates.
Effect of addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs
Authors: Nomura M , Kubota M A , Kawamori R , Yamasaki Y , Kamada T , Abe H
Published: April 2011

Insulin absorption from the conjunctiva was investigated in five pancreatectomized diabetic mongrel dogs, with the nasolacrimal ducts occluded by micro plugs to prevent insulin absorption from nasolacrimal membrane. In the anaesthetized state, highly concentrated porcine insulin (1000 units mL−1, pH7·4) was absorbed rapidly and significantly from the conjunctiva. Plasma immunoreactive insulin concentrations increased significantly up to 3 h after insulin administration to conjunctival membranes. Plasma glucose concentration decreased significantly compared with saline control experiments after insulin administration (10 units kg−1) at 3 h (8·3 ± 0·1 vs 15·6 ± 0·6 mmol, P < 0·01). However, in the conscious state, there was no significant increase in the plasma insulin levels after topical insulin administration. To improve insulin absorption in the conscious state, we examined the effect of increasing viscosity of insulin preparation with hyaluronic acid. In anaesthetized experiments, there were no significant changes in the bioavailability of insulin after addition of hyaluronate (0·84 ± 0·11 vs 0·87 ± 0·05%). In the conscious state, with addition of hyaluronic acid, the area under the curve of plasma insulin concentration was significantly increased (1842 ± 383 vs 75 ± 24 m units min L−1, P < 0·01). The bioavailability of insulin absorption was significantly increased after addition of hyaluronate (0·68 ± 0·14 vs 0·03 ± 0·01%, P < 0·01). From this study we could demonstrate that the conjunctiva is a potential route for insulin administration, and increased viscosity by the addition of hyaluronate was found effective in increasing the bioavailability of insulin absorption from conjunctival membrane in the conscious state.
Tissue- and subcellular-distribution of the binding site of [3H]9-methyl-7-bromoeudistomin D, a potent caffeine-like Ca2+ releaser, in rabbits
Authors: Adachi Masatoshi , Kakubari Masae , Ohizumi Yasushi
Published: April 2011

Tissue and subcellular distribution of the binding site of 3H-labelled 9-methyl-7-bromoeudistomin D ([3H]MBED), a powerful caffeine-like Ca2+ releaser, were investigated in rabbits. The order of specific activities of total homogenates was liver > brain > other tissues. All binding was completely suppressed by 10 Mm caffeine, indicating that all [3H]MBED binding sites are modulated by caffeine. [3H]MBED binding sites distributed mainly in membrane fractions rather than soluble fractions in most tissues. In lung and liver, [3H]MBED binding was enriched in microsomes. [3H]MBED may be useful as a probe to investigate the actions of caffeine at the molecular level not only in muscles but also in a variety of tissues including liver, kidney and lung.
The Effect of TYB-2285 on Dual Phase Bronchoconstriction and Airway Hypersensitivity in Guinea-pigs Actively Sensitized with Ovalbumin
Authors: Muraki M , Tohda Y , Sugihara R , Nagasaka Y , Nakajima S
Published: April 2011

The effect of a new anti-asthmatic drug, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chloro-benzonitrile), was investigated in ovalbumin-sensitized guinea-pigs. When guinea-pigs were pretreated with TYB-2285 (300 mg kg−l, p.o., single dose or consecutively for 7 days), the immediate asthmatic response was inhibited as demonstrated by diminished cyanosis, but not the bronchoconstriction. TYB-2285, given singly or consecutively, inhibited the appearance of late asthmatic response and the infiltration of inflammatory cells, such as eosinophils, into the airway. Additionally, airway hyper-responsiveness was also reversed by the single administration of TYB-2285. Luminol-dependent chemiluminescence of airway-infiltrated cells stimulated with A23187 was inhibited by TYB-2285 in a dose-dependent manner. The present study suggests that TYB-2285 inhibits late asthmatic response and airway hyper-responsiveness by inhibiting the accumulation of eosinophils and other inflammatory cells into the airway, and also by inhibiting the production of oxygen radicals from airway-infiltrated cells.
Endotoxin-induced Fever Increases the Clearance of Methohexitone in Rabbits
Authors: Redke Finn , Björkman Sven
Published: April 2011

We have previously observed that the clearance of methohexitone, given by continuous infusion for sedation in the intensive care unit, was influenced by body temperature in patients with post-operative fever. The aim of the present study was to reproduce this finding in an animal model that can then be used to predict similar influences for other anaesthetic agents. Sixteen rabbits were infused for 2·0 h with methohexitone (8·4 ± 0·5 mg kg−1 h−1 (mean ± s.d.)) and in eight of them fever was induced with intravenous Escherichia coli endotoxin. Arterial blood samples were taken over 6 h and plasma concentrations of methohexitone were assayed by gas chromatography. The mean body temperatures of the rabbits over the periods of measurement varied between 38·5 and 41·8°C, and the total clearance of methohexitone (mean 50·7 mL min−1 kg−1) was positively correlated with temperature (r = 0·545, P = 0029). No significant correlations with temperature were found for other pharmacokinetic parameters. We conclude that these observations correspond to the findings in the clinical pharmacokinetic study, showing the validity of the animal model.
In-vitro Smooth Muscle Relaxant Activity of a Series of Vecuronium Analogues in the Rat Aorta
Authors: Fiddes Shaun , Prior Chris
Published: April 2011

The ability of a series of 17-ester analogues of vecuronium to elicit a direct relaxant effect on vascular smooth muscle has been studied using rat isolated aortic rings contracted with 40 mm KCl. The IC50 for inhibition of KCl-induced contractions increased with increasing size of the 17-ester substituent, such that vecuronium (17β-acetate) was the least potent with an IC50 of around 500 μm and Org-9827 (17α-pivalate) was the most potent with an IC50 of around 5 μm. In addition, for the weaker-acting compounds, the 17α-esters were more potent than their corresponding 17β-esters, although this difference was lost as the size of the 17-ester substituent increased. From the results obtained here, it is concluded that the hypotensive activity of some of the newer neuromuscular blocking steroids seen in cats, pigs and dogs in-vivo is probably, at least in part, a consequence of a direct relaxant effect of the compound on vascular smooth muscle through inhibition of voltage-activated, L-type, calcium channels. This may have both advantageous and disadvantageous clinical consequences when using large doses of one of the newer vecuronium analogues with a low relative neuromuscular-blocking potency.
Mammary excretion of cannabidiol in rabbits after intravenous administration
Authors: Yoo S D , Fincher T K , Holladay J W
Published: April 2011

The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg−1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4–24-h period following the maternal injection. The mean milk to serum concentration ratio was 25·9, indicating a significant accumulation of the drug in milk.
Comparison of distribution of brush-border exo- and endopeptidases in rat and rabbit intestine
Authors: Bai Jane P F
Published: April 2011

The distribution of brush-border endopeptidase-2, aminopeptidase W, carboxypeptidase P, and aminopeptidase P along the rat and rabbit intestine was examined. In both species, aminopeptidases P and W increased distally and reached the highest in the ileum; their activities in the ileo-caecal junction were the lowest. Endopeptidase-2 had a uniform intestinal distribution in both species with the highest activity in the ileum and little activity in the ileo-caecal junction or caecum. With a distribution similar to that of endopeptidase-2, carboxypeptidase P also had high activity in the ileum in rats and rabbits.
The inhibitory effect of amiodarone and desethylamiodarone on dextromethorphan O-demethylation in human and rat liver microsomes
Authors: Jaruratanasirikul Sutep , Hortiwakul Ratri
Published: April 2011

Amiodarone has been shown in-vitro to inhibit the activity of cytochrome P4502D6 (CYP2D6) in nonhuman primates. However, the influence of its major metabolite, desethylamiodarone, on this isozyme activity has not been studied. To determine the effect of these drugs on dextromethorphan O-demethylation, we carried out studies in 10 human and 10 rat liver microsomal preparations. In human microsomal studies, amiodarone and the metabolite competitively inhibited dextromethorphan metabolism with mean Ki values of 52·70 ± 5·27 and 34·40 ± 3·30 μm, respectively. Similar studies in rat microsomes showed a competitive inhibitory effect of amiodarone and its metabolite on dextromethorphan metabolism. These data suggest that amiodarone and desethylamiodarone have an inhibitory effect on CYP2D6 in man and CYP2D1 in rats. However, it cannot be concluded that both of them are substrates of this isozyme activity.
Scintigraphic Assessment of the Oropharyngeal and Nasal Depositions of Fusafungine from a Pressurized Inhaler and from a Novel Pump Spray Device
Authors: Newman S P , Steed K P , Hooper G , Brickwell J
Published: April 2011

The distributions of fusafungine (Locabiotal, Servier) radiolabelled with 99mTc, and delivered either orally or intranasally, have been assessed in healthy volunteers from a pressurized metered-dose aerosol inhaler (125 μg per dose) and from a novel mechanical pump spray device (500 μg per dose).

More than 90% of the dose was initially deposited in the oropharynx for oral dosing (n = 8), and more than 90% in the nose for nasal dosing (n = 9), with no significant penetration of aerosol into the lungs. Although not statistically significant, the mean area of deposition, measured in terms of gamma camera picture elements (pixels), was greater with the pump spray for both oral and nasal dosing. The area of deposition with the nasal pump spray extended into the turbinates in six of nine subjects, compared with only three of nine subjects for the pressurized aerosol.

The data suggest that the distribution patterns of pump sprays and pressurized aerosols of fusafungine in the oropharynx and in the nasal passages are similar, and that the former can be substituted for the latter with little change in drug delivery.
Bioavailability of Bropirimine 250 mg Tablet in Dogs: Effect of Food
Authors: Emori Hisatoshi , Yamamoto Ken , Yokohama Shigeharu , Nishihata Toshiaki
Published: April 2011

The postprandial effect on the bioavailability of bropirimine in dogs after oral administration of bropirimine tablets (Bropirimine 250 mg Tablet) was investigated.

At a dose of 500 mg bropirimine (two tablets of bropirimine 250 mg), the maximum plasma concentration under the postprandial condition was about twice that observed under the fasting condition, and the area under the plasma concentration vs time curve under the postprandial condition was also twice that under the fasting condition. The absolute oral bioavailabilities of bropirimine were 41.1% under the fasting condition and 83.5% under the postprandial condition.

It is considered that the longer gastric residence time and larger volume of the gastric fluid induced by food-intake caused the increase in dissolution of bropirimine which increased the bioavailability after oral dosing of bropirimine 250-mg tablets.
Metabolism of Beclamide after a Single Oral Dose in Man: Quantitative Studies
Authors: Ahmadi M , Nicholls P J , Smith H J , Spencer P S J , Preet-Ryatt M S , Spragg B P
Published: April 2011

A simple reverse phase HPLC assay is described for the determination of the anticonvulsant compound, beclamide and its 3- and 4-hydroxyphenyl metabolites in urine.

Following oral administration of 1 g beclamide to a panel of healthy volunteers, less than 0.4% of the dose was excreted unchanged in the 24-h urine and unconjugated 3- and 4-hydroxyphenyl metabolites were not detected. Based on examination of the urine after incubation with β-glucuronidase and aryl sulphatase, it was found that these hydroxyl metabolites were excreted as both glucuronide and sulphate conjugates. For each metabolite the glucuronide was the major excretory product (approximately 10: 1). The 24-h excretion of the combined conjugated metabolites was 7% (for the 3-hydroxy metabolite) and 24% (for the 4-hydroxy metabolite) of the dose. Approximately 22% of the administered dose of beclamide was excreted as hippuric acid.

In view of the simplicity of assay, beclamide may be a useful tool substance with which to examine factors influencing the xenobiotic metabolic pathways of benzene ring hydroxylation and glucuronide and sulphate conjugation in man.
Aggregation of Proteins and its Prevention by Carbohydrate Excipients: Albumins and γ-Globulin
Authors: Katakam Manohar , Banga Ajay K
Published: April 2011

Moisture-induced (2–10 μL added to 10mg) aggregation of solid-state albumin and γ-globulin was investigated by incubation at 37°C for 24 h.

The insoluble aggregates were centrifuged from a reconstituted solution, dissolved in a solution containing denaturant and reducing agent, and analysed by a Bio-Rad protein assay kit. Of the three albumins used, maximum aggregation (8·2%) was observed with bovine serum albumin that was essentially fatty-acid free. The maximum aggregation observed with γ-globulin was 70%. A bell-shaped curve for percent aggregation was observed with increasing moisture content and was especially prominent for bovine serum albumin. When mixed with carbohydrate excipients in a 1:1 ratio, aggregation was reduced for both bovine serum albumin and γ-globulin by all four of the following excipients used: Emdex, dextrose, trehalose and hydroxypropyl β-cyclodextrin. For bovine serum albumin, the aggregation was reduced about sixfold, with Emdex being the most effective excipient.

The likely mechanism of the resulting aggregation was covalent linkages formed due to intermolecular thiol disulphide interchange.
Preparation and Characterization of 5-Fluorouracil-loaded Microparticles as Biodegradable Anticancer Drug Carriers
Authors: Boisdron-Celle M , Menei PH , Benoit J P
Published: April 2011

To provide a device releasing 5-fluorouracil in a controlled manner and injectable into the brain by stereotaxy, biodegradable poly ((±)-lactide-co-glycolide) (PLAGA) microparticles were prepared by an emulsion-extraction process.

Although the solubility profile of the drug was not suitable for its encapsulation by the aforementioned method, careful choice of process variables allowed significant drug loading, reaching 30%. Thus, the size of the 5-fluorouracil crystals, the organic phase/aqueous phase ratio, the theoretical drug loading and the microparticle size played a predominant role. The microsphere size was adjusted to 20–40 μm by selecting the appropriate PLAGA and polyvinylalcohol concentrations, and the stirring rate of the initial emulsion.

It was shown that the microparticle structure depended directly on the experimental conditions governing the precipitation rate of the coating material: two types of microparticles, I and II, were characterized. The morphology of the particles influenced the 5-fluorouracil-release patterns, as did other process parameters, such as the 5-fluorouracil crystal size and the PLAGA concentration.

It was possible to sustain the 5-fluorouracil release over 18 days.
Differential Effects of Modified β-Cyclodextrins on Pharmacological Activity and Bioavailability of 4-Biphenylacetic Acid in Rats after Oral Administration
Authors: Puglisi G , Ventura C A , Spadaro A , Campana G , Spampinato S
Published: April 2011

Gastric tolerability, absorption and pharmacological activity of the non-steroidal anti-inflammatory drug 4-biphenylacetic acid (BPAA), as an inclusion complex with β-cyclodextrin (β-CyD) or chemically modified β-CyDs: 2,6-di-O-methyl-β-CyD (DM-β-CyD), 2,3,6-tri-O-methyl-β-CyD (TM-β-CyD) and 2-hydroxypropyl-β-CyD (HP-β-CyD), were investigated in the rat after oral administration.

BPAA absorption, determined from area under the plasma concentration-time curve (AUC), was increased by complexation with all β-CyDs in the following order: DM-β-CyD > TM-β-CyD > HP-β-CyD > β-CyD. The carrageenan paw oedema test demonstrated a significant increase in anti-inflammatory activity of BPAA and the ED50 values, compared with BPAA alone, were reduced to about a third for the BPAA-DM-βCyD complex and halved for the others. BPAAA complexed with DM-β-CyD, HP-β-CyD or β-CyD showed better gastric tolerability compared with uncomplexed drug, whereas the BPAA-TM-β-CyD complex produced marked gastric lesions similar in extent to BPAA alone. TM-β-CyD (500mg kg−1) and DM-β-CyD (1000mg kg−1) caused gastric erosions 21 h after oral administration.

The pharmacokinetic profiles of BPAA-β-CyD complexes have shown that DM-β-CyD is the most effective in enhancing the bioavailability of BPAA.
Novel 1,4 Substituted Piperidine Derivatives. Synthesis and Correlation of Antioxidant Activity with Structure and Lipophilicity
Authors: Alexidis Alexandros N , Rekka Eleni A , Demopoulos Vassilis J , Kourounakis Panos N
Published: April 2011

A series of novel piperidine derivatives was prepared and their lipophilicity was determined (as RM values). These compounds as well as two intermediate α-keto-esters were tested for antioxidant activity.

It was found that the cysteamine derivatives were efficient antioxidants, i.e. they could inhibit lipid peroxidation, act as hydroxyl radical scavengers and interact with 2,2-diphenyl-l-picrylhydrazyl radicals. This interaction could be attributed to the free SH group and this activity seemed to be favoured by increased lipophilicity.

Replacement of SH by NH2 or OH resulted in a decreased antioxidant activity of the compounds. However, the described activities seem not to be connected with any O−2· scavenging ability, at least under the experimental conditions applied. Furthermore, cysteamine derivatives seem to induce O−2· generation, a phenomenon often observed with thiol compounds.

The antioxidant activity of the intermediate α-keto-esters varied and is probably mediated by different mechanisms.
Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure, in Mice
Authors: Rubat Catherine , Coudert Pascal , Bastide Pierre , Tronche Pierre
Published: April 2011

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice.

The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg−1. Only at intraperitoneal doses of 100mg kg−1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg−1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg−1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg−1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg−1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg−1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg−1, s.c). At 200 mg kg−1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg−1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg−1, i.p.) in mice pretreated with pargyline (100mg kg−1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg−1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg−1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg−1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg−1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg−1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg−1 for PC4 and 5mg kg−1 for PC13) potentiated morphine (7–5 mg kg−1, s.c.) analgesia in the hot-plate test.

Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT2 receptor level.
Plasma and Cerebrospinal Fluid Concentrations of Morphine and Morphine Glucuronides in Rabbits Receiving Single and Repeated Doses of Morphine
Authors: Mignat Christian , Jansen Ruth , Ziegler Albrecht
Published: April 2011

The pharmacokinetics of morphine in plasma and the distribution of morphine and its glucuronidated metabolites within the cerebrospinal fluid were investigated in rabbits.

After single morphine dosage, the plasma AUC ratio of morphine-3-glucuronide/morphine was 11·1 compared with 0·14 for morphine-6-glucuronide/morphine. The similar elimination half-lives of morphine (107 min), morphine-3-glucuronide (122 min), and morphine-6-glucuronide (105 min) suggested the glucuronidation to be the rate-limiting step, which was substantiated by the observation that morphine-3-glucuronide becomes eliminated four times faster when applied intravenously. Both after single and repeated morphine administration, the ratios of CSF and plasma levels of the parent drug were higher than those of morphine-3-glucuronide or morphine-6-glucuronide.

These data demonstrate a poor penetration of the glucuronides across the blood-brain barrier and do not support the previously postulated accumulation of morphine-6-glucuronide in the central nervous system during chronic morphine treatment.
Epidemiology and Susceptibilities to Mercury Preservatives of Staphylococci Isolated from Used Eye-Drops Preserved with Thiomersal
Authors: Du Bois S K , Davison A L , Pinney R J
Published: April 2011

Minimum inhibitory concentrations (MICs) of seven independent isolates of Staphylococcus hominis isolated in the same week from used eye-drops, preserved with thiomersal and collected from wards and clinics in the same hospital, ranged between 1 and 0·03 mg L−1 for thiomersal, 1 and 0·01 mg L−1 for phenyl mercuric nitrate and 10 and 3 mg L−1 for mercuric chloride.

Although MIC values determined on solid nutrient medium indicated a 100-fold variation in susceptibility to the bacteriostatic effect of phenyl mercuric nitrate, after 5 h in an aqueous solution containing the bactericidal concentration of 10 mg L−1 phenyl mercuric nitrate, the survival levels of the six S. hominis isolates were similar, with a mean of 13·4% (s.d. 11·0), compared with 100 and 0·8%, respectively, for the most resistant and most sensitive control staphylococcal strains tested. Antibiotic susceptibilities and plasmid profiles of the S. hominis isolates indicated they were the same strain.

It is concluded that laboratory indicators of preservative efficacy, such as MIC determination or susceptibility to bactericidal concentrations of preservatives, do not necessarily correlate with the epidemiology of contaminating bacterial strains or their survival in preserved pharmaceuticals.
Transdermal Delivery of Physostigmine. A Pretreatment Against Organophosphate Poisoning
Authors: Jenner J , Saleem A , Swanston D
Published: April 2011

Physostigmine absorption through isolated human skin and inhibition of plasma and red blood cell cholinesterases in guinea-pigs have been measured to assess the feasibility of its transdermal delivery as a pretreatment for organophosphate poisoning.

Penetration of radiolabeled physostigmine across human epidermis was measured in-vitro using glass diffusion cells and optimization of physostigmine delivery was achieved by changes in vehicle formulation and use of penetration enhancers.

Two-component vehicles consisting of propionic acid/isopropyl myristate (50:50) and propionic acid/oleic acid (50:50) produced the highest transdermal delivery of physostigmine. A comparison of formulations containing propionic acid alone with propionic acid plus oleic acid when applied to guinea-pigs, showed that inclusion of oleic acid allowed the amount of physostigmine and the size of the transdermal patch to be substantially reduced, whilst maintaining effective delivery rates. The formulation containing oleic acid was not irritant to guinea-pigs when applied to the skin for 48 h.

It is concluded that a mixture of propionic acid and oleic acid containing physostigmine is a good candidate for transdermal delivery of physostigmine as a pretreatment for organophosphate poisoning.
Do 5-HT4 Receptors Mediate the Intestinal Secretory Response to 5-HT in Rat In-vivo?
Authors: Franks C M , Hardcastle J , Hardcastle P T , Sanger G J
Published: April 2011

The involvement of the recently characterized 5-HT4 receptor in the actions of 5-hydroxytryptamine (5-HT) on jejunal, ileal and colonic electrogenic ion secretion was investigated in the rat in-vivo.

5-HT and the 5-HT1-, 5-HT2- and 5-HT4-receptor agonist 5-methoxytryptamine (5-MeOT), induced a rise in transintestinal PD in all regions of the gut. However, the 5-HT4-receptor agonists renzapride and cisapride had no effect. Furthermore, the 5-HT4-receptor antagonists SDZ 205–557 (2-diethylaminoethyl-[2-methoxy-4-amino-5-chloro] benzoate), tropisetron and SB 204070 ([1-butyl-4-piperidinylmethyl]-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate hydrochloride) did not affect the secretory response to either 5-HT or 5-MeOT in the jejunum, but did cause a small inhibition in the ileum and colon.

It is concluded that 5-HT4 receptors do not make a contribution to the electrically monitored 5-HT intestinal secretory response in the rat jejunum in-vivo, but may play a small role in the ileum and colon.
Amelioration of Cisplatin Nephrotoxicity with Glycine: Dose Dependency in Rats
Authors: Li Q , Bowmer C J , Yates M S
Published: April 2011

The effects of glycine (0·1-1·0 g μg kg−1, i.v.) on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin (6·0 mg g kg−1, i.v.) were investigated in the rat.

Cisplatin produced decreases of 50% in the clearance of [3H] inulin (CIN) and renal blood flow (RBF), 110 min following its injection. Glycine at a dose of 0·1 g kg−1 produced no attenuation of the cisplatin-induced decrease in CIN or RBF. Furthermore, this dose of glycine provided no significant protection of renal function over a 7-day period following cisplatin injection.

By contrast, glycine at a dose of either 0·5 or 1·0 g kg−1 markedly attenuated cisplatin-induced falls in CIN and RBF, with the highest dose completely preventing any falls in these indices during the course of the experiment. Treatment with these higher doses of glycine produced prominent protection from the nephrotoxic actions of cisplatin, as evidenced by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, CIN and the clearance of [14C]P-aminohippurate.

The results of experiments with an intermediate dose of 0·25 g kg−1 glycine revealed some degree of amelioration of acute renal haemodynamic effects of cisplatin, particularly with regard to CIN; whilst in the nephrotoxicity study, 0·25 g kg−1 glycine produced a modest but significant reduction in cisplatin-induced acute renal dysfunction.

The results have revealed a clear association between the acute renal haemodynamic effects produced by glycine in cisplatin-injected rats with the longer-term renal protective effects of glycine in cisplatin nephrotoxicity. The findings indicate that glycine's ability to prevent the falls in RBF and glomerular filtration rate produced by cisplatin plays an important role in the protective effect of glycine in cisplatin-induced nephrotoxicity.
Correlation of Pharmacological Properties of a Group of β-Blocker Agents by Molecular Topology
Authors: Garcá-March F J , Cercós-Del-Pozo R A , Pérez-Giménez F , Salabert-Salvador M T , Jaén-Oltra J , AntÓn-Fos G M
Published: April 2011

The molecular connectivity method has been applied to the study of pharmacological properties, among which are found the angor treatment dose, α-distribution half-life and intravenous LD50 in mouse, of a group of β-blocker agents, verifying its application in the prediction of theoretic values for said pharmacological properties.

To do this, the obtained multiple regression functions of the corresponding connectivity indices were used in relation with the experimental values of the properties, which are accompanied by the statistical parameters used in their selection criteria, as well as the corresponding random and cross-validation studies of said functions, which corroborate the good correlation of the selected equations.
Inhibitory Effect of 5-Hydroxytryptamine on Rat Stomach Fundus: Mediated Indirectly by Activation of Noradrenaline Release
Authors: Béjar E , Malone M H
Published: April 2011

Biphasic cumulative concentration-response curves to 5-hydroxytryptamine (5-HT) and α-methyl-5-hydroxytryptamine (α-Me-5-HT) using rat stomach fundus in the presence of 50 μm pargyline suggested two sites of interaction (high and low affinity).

The order of agonist potencies of 5-HT agonists for the high-affinity (contractile) response confirmed reports of a strong correlation of the 5-HT2B (contractile) receptor on fundus with reported rat brain (radioligand binding) pKd values at the 5-HT2C receptor (r = 0·94, b = 0·93 P < 0·01). 1(1-Naphthyl)-piperazine and ketanserin antagonized the high-affinity responses. The order of potencies for the low affinity (inhibitory) response was: α-Me-5-HT > 5-HT. Preincubation with mianserin or S-(—)propranolol, pretreatment with reserpine and removal of the mucosa layer resulted in amplification of the contractile effects and disappearance or reversal of the inhibitory effects of 5-HT.

Activation of a second receptor site inducing catecholamine release may explain this effect of 5-HT on rat stomach fundus.
Relaxant Activity of Three Aporphine Alkaloids from Annona cherimolia on Isolated Aorta of Rat
Authors: Chuliá S , Ivorra M D , Cavé A , Cortés D , Noguera M A , D'Ocón M P
Published: April 2011

In the present study we tested the relaxant effect of three aporphine alkaloids—roemerine, anonaine and dehydroroemerine—isolated from the roots of Annona cherimolia, on isolated strips of rat thoracic aorta.

All compounds completely relaxed KCl- and noradrenaline-induced contractions with different potencies depending on their structural characteristics. The experiments, carried out in Ca2+-free medium using two different agonists (noradrenaline and caffeine) which mobilize calcium intracellularly by different mechanisms of action, showed that the alkaloids made no contribution to intracellular calcium processes.

The present study provides evidence that the relaxant effects produced by aporphine alkaloids may be due to the blockade of calcium movements across the cell membrane, mainly through voltage-operated channels, and to the disruption of α1-adrenoceptors connected to receptor-operated channels.