bluuebunny/crossref_metadata_2025 huggingface dataset:
Increase in susceptibility to EcoRII restriction of bacteriophage λ produced by propagation on host cells growing in 5-azacytidine: a new in-vivo method for demonstration of DNA-methylation inhibition
Authors: Radnedge L , Pinney R J
Published: April 2011

The efficiency of plating on EcoRII-restricting cells of bacteriophage λvir propagated on an Escherichia coli K-12 dcm+ host decreased with increase in concentration of 5-azacytidine (5-azaC) in the propagating medium. This illustrates, in-vivo, the inhibition of DNA-cytosine methylation induced by 5-azaC and provides a simple system for the detection of DNA-methylation inhibitors.
Prediction of Skin Permeability of Drugs: Comparison of Human and Hairless Rat Skin
Authors: Morimoto Yasunori , Hatanaka Tomomi , Sugibayashi Kenji , Omiya Harumi
Published: April 2011

Relationships between skin permeability and physicochemical properties of drugs were examined to establish a predictive method for the steady-state permeation rate of drugs through human skin. Human skin permeation properties fell into two categories: one in which the permeability coefficient is correlated to the partition coefficient, revealed with lipophilic drugs; and the other in which the permeability coefficients are almost constant, shown with hydrophilic drugs. The stratum corneum, the main barrier in skin, could be considered as a membrane with two parallel permeation pathways: lipid and pore pathways, and an equation for predicting the steady-state permeation rate of drugs was derived. The skin permeabilities of drugs for man were compared with those for hairless rat. The species difference in skin permeability found was suggested to be due to the difference in skin permeation pathways, since lipid content and water uptake of the stratum corneum varied between human and hairless rat skin.
Concentration-dependent Exsorption of Quinidine in the Rat Intestine
Authors: Bair Chi-Horng , Tang Ming-Jer , Huang Jin-Ding
Published: April 2011

During intravenous infusion, the luminal concentration of quinidine was higher than the plasma concentration. The intestinal clearance (CLi) of the drug was measured by dividing the rate of appearance of the drug in the intestinal luminal perfusate by the plasma concentration. The CLi of quinidine was therefore much higher than the rate of luminal perfusion. Over the infusion dose range of 0·1–2 mg h−1, the CLi of quinidine decreased with increasing plasma concentration of quinidine. Adding quinidine into the luminal perfusate had little effect on the CLi of quinidine. Co-administration of quinidine with other agents intravenously did not alter the CLi of salicylic acid and urea, while the same treatment decreased the CLi of theophylline and 5-disopyramide. In-vitro experiments on brush-border membrane vesicles showed that quinidine decreased the rate of Na+ uptake and H+ efflux. The inhibition was significant at quinidine concentrations above 20 μm. Quinidine was a more potent inhibitor than amiloride. At quinidine infusion rates less than 2 mg h−1, quinidine concentration in plasma or in the luminal perfusate was at the lower limit of the inhibitory concentration. Microclimate pH at the intestinal surface was also measured. At mid-jejunum, the microclimate pH increased 0·3 pH units by infusing 2 mg h−1 of quinidine, while the microclimate pH at most other measuring sites was not significantly altered by quinidine infusion. It was concluded that quinidine is exsorbed from blood into the intestinal lumen by a carrier-mediated pathway in addition to the passive diffusion. At high plasma concentration, quinidine exsorption becomes saturated. Quinidine inhibited the intestinal exsorption of theophylline and S-disopyramide possibly by competition on the carrier.
Vasorelaxation of Rat Thoracic Aorta Caused by Two Ca2+-Channel Blockers, HA-22 and HA-23
Authors: Yu Sheu-Meei , Kuo Sheng-Chu , Huang Li-Jiau , Sun Selma Siu-Man , Huang Tur-Fu , Teng Che-Ming
Published: April 2011

The pharmacological effects of HA-22 (2-(4′methoxyphenylmethyl)-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H)-one) and HA-23 (2-(2′-thienylmethyl)-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H)-one) on rat isolated thoracic aorta have been examined. In high potassium medium (60 Mm), Ca2+ (0·03–3 Mm)-induced vasoconstriction was inhibited by HA-22 and HA-23 (10–100 μg mL−1). Cromakalim-relaxed aortic rings precontracted with 15 Mm but not 60 Mm K+. However, HA-22, HA-23 and verapamil produced a greater relaxation in 60 Mm than in 15 Mm K+-induced contraction. The tonic contractions elicited by KCl (60 Mm) and Bay K 8644 (10−7  m) were also relaxed by the addition of HA-22 and HA-23. The phenylephrine concentration-response curves displayed antagonism by HA-22 and HA-23 (10–100 μg mL−1) in a non-competitive manner. The caffeine (10 Mm)-induced contraction and cAMP or cGMP levels were not affected by HA-22 or HA-23. It is concluded that HA-22 and HA-23 relaxed the rat aorta by suppressing the Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ channels.
Urinary Excretion of Ephedrine After Nasal Application in Healthy Volunteers
Authors: Lefebvre R A , Surmont F , Bouckaert J , Moerman E
Published: April 2011

The urinary excretion of ephedrine after intranasal administration of the drug was studied in 8 healthy volunteers. Ephedrine (6 drops of a commercial 0·75% nasal ephedrine solution in each nasal cavity) was administered 4 times at intervals of 2 h (total amount applied equivalent to approximately 14 mg ephedrine), and urine was collected each hour for 10 h; the volunteers exercised on a bicycle ergometer at 50% of their V̊O2max for 2 h after the last ephedrine application. Ephedrine was detected in all urine samples. The urinary ephedrine concentration ranged from 0·9 to 16–5 μg mL−1; the number of urine samples with an ephedrine concentration exceeding 5 μg mL−1 ranged from 1/10 (volunteer 2) to 9/10 (volunteers 1 and 3). The mean percentage of dose recovered within 10 h was 33% (range 23–50%). There was a weak but significant negative correlation between urinary pH and amount of ephedrine in the urine; exercise did not consistently influence the urinary amount. These results illustrate the systemic availability of ephedrine upon intranasal administration and show that the therapeutic use of a nasal ephedrine formulation by an athlete on the day of a competition can lead to a urinary ephedrine concentration above 5 μg mL−1, which is considered positive in current doping regulations of the International Union of Cyclists.
Comparison of salivary fluoride concentrations after administration of a bioadhesive slow-release tablet and a conventional fluoride tablet
Authors: Bottenberg P , Cleymaet R , De Muynck C , Remon J P , Coomans D , Slop D
Published: April 2011

The in-vitro and in-vivo fluoride release of bioadhesive, slow-release tablets prepared from a mixture of polyethylene glycol polymers, containing 0·1 mg of fluoride as NaF was studied, and their ability to sustain fluoride levels in saliva were compared with conventional fluoride tablets with the same fluoride content. In-vitro release experiments showed that the bioadhesive tablets needed 8 h to release all their fluoride compared with < 1 h for the conventional fluoride tablets. In-vivo, the bioadhesive tablets had a retention period of 6 h and could sustain a salivary fluoride level of more than 10 μm above the baseline for 7 h. The conventional fluoride tablets achieved a peak concentration of 0·5 Mm directly after dissolution in the mouth, but the fluoride level could not be sustained for longer than 1 h. A good agreement was found between the in-vitro swelling behaviour of the bioadhesive tablets and their in-vitro and in-vivo release characteristics and their in-vivo retention time.
HI-6 pharmacokinetics in rabbits after intravenous and intramuscular administration
Authors: Lukey B J , Woodard C L , Clark C R , Mccluskey M P
Published: April 2011

The pharmacokinetics of HI-6 ((4-carboxamidopyridinium (1) methyl)-(2′-hydroxyiminomethyl-pyridinium (1′) methyl) ether dichloride) have been studied in rabbits receiving an intramuscular (50 μg kg−1) or intravenous (12·5 μg kg−1) dose. The plasma concentration-time profile for the intramuscular dose (n = 8) fits a one-compartment open model with first-order absorption and elimination. The absorption half-life was 2 min and maximum concentration (51 μg mL−1) was reached in 9 min. The pharmacokinetics for the intravenous dose (n = 8) was described by a two-compartment open model with first-order distribution and elimination. The apparent volume of distribution was 0·1 Lkg−1. Half-lives of distribution and elimination were 5 and 38 min, respectively. The results indicate HI-6 is rapidly absorbed, distributed and eliminated in rabbits receiving an intramuscular dose.
The pH Dependent Uptake of Enoxacin by Rat Intestinal Brush-border Membrane Vesicles
Authors: Iseki Ken , Hirano Takeshi , Fukushi Yuko , Kitamura Yukie , Miyazaki Shozo , Takada Masahiko , Sugawara Mitsuru , Saitoh Hiroshi , Miyazaki Katsumi
Published: April 2011

The mechanism of the intestinal transport of enoxacin, an orally active fluoroquinolone antibiotic, has been investigated using brush-border membrane vesicles isolated from rat small intestine. The initial rate and time-course of enoxacin uptake were considerably dependent upon the medium pH (pH 5·5 > pH 7·5) and upon the percent ionization of the carboxyl group (pKa 6·2, anionic charge), namely, the degree of uptake of cationic form was higher than that of the zwitterionic form. There was evidence of transport into the intravesicular space as shown by the effect of extravesicular medium osmolarity on enoxacin uptake at steady state (30 min). This transport across the brush-border membrane was stimulated by the valinomycin-induced K+-diffusion potential (interior negative) and an outward H+-diffusion potential. Furthermore, changing the pH of the medium from 5·5 to 7·5 significantly decreased the effect of valinomycin-induced K+-diffusion potential on the enoxacin uptake. These results suggest that the uptake behaviour of the cationic form of enoxacin plays an important role in the intestinal absorption process of enoxacin.
Distribution of antipyrine in the rat liver
Authors: Hussein Ziad , Rowland Malcolm
Published: April 2011

The rate and extent of hepatic distribution of antipyrine was examined in the rat isolated perfused liver. Tritiated water and [14C]antipyrine were injected simultaneously into the portal vein as a bolus using either Krebs-Ringer bicarbonate or rat plasma as the perfusate. The effluent profiles of each compound using the two perfusates were superimposable, a finding expected for water and consistent for antipyrine, which was negligibly bound in rat plasma. Although full recovery (97%) of administered material was achieved with both compounds, the fractional output profile for antipyrine peaked at a lower value (0·10 mL−1) and at a later time (24 s) than water (0·14 mL−1, 17·5 s), due to antipyrine having a larger volume of distribution (water 0·61 mL (g liver)−1); antipyrine 0·81 mL (g liver)−1). This observation is explained by antipyrine binding to, or partitioning into cellular components. Nonetheless, like water, distribution of antipyrine into hepatic cells is perfusion rate limited as evidenced by the superimposition of the dimensionless plots of fractional output vs time normalized to mean residence time.
Accumulation of Polyvinylpyrrolidone within the Inflamed Paws of Adjuvant-induced Arthritic Rats
Authors: Seale L , Love W G , Amos N , Williams B D , Kellaway I W
Published: April 2011

125I-Labelled polyvinylpyrrolidone ([125I]PVP) of a range of molecular weights (mol. wt 10, 40 and 360 kDa) was injected i.v. into adjuvant-induced arthritic and normal rats and the blood clearance and tissue distribution of the polymers determined. The half-life of PVP in the circulation increased with increasing mol. wt; 10, 40 and 360 kDa polymers had mean terminal half-lives of 2·2, 6·9 and 16·4 h, respectively. Tissue uptake was also found to be mol. wt dependent, the largest PVP molecule accumulating to a greater extent in the spleen, liver, lungs and paws in both normal and arthritic rats (P < 0·01) than the two lower mol. wt polymers. Accumulation of the polymer in inflamed paws (g tissue)−1 greatly exceeded that of normal paws (P < 0·01). This difference was particularly noticeable with 360 kDa PVP, where arthritic paws amassed 7 times more PVP than normal paws.
Diuretic Action of the Novel Loop Diuretic Torasemide in the Presence of Angiotensin II or Endothelin-1 in Anaesthetized Dogs
Authors: Uchida Takeshi , Hayashi Kazutaka , Kido Hideaki , Watanabe Masahiro
Published: April 2011

The effects of torasemide (0·1 and 1 mg kg−1, i.v.) and furosemide (3 mg kg−1) on renal haemodynamics and excretory responses in the presence of angiotensin II and endothelin-1 was examined in anaesthetized dogs. Angiotensin II or endothelin-1 was continuously infused into the renal artery throughout the experiment and a bolus of torasemide or furosemide was injected into the bracheal vein. Continuous intrarenal arterial (i.r.a.) infusion of angiotensin II, at a dose of 5 ng kg−1 min−1, increased renal vascular resistance (RVR) and decreased renal blood flow (RBF) and glomerular filtration rate (GFR), but had no effect on systemic mean arterial pressure (MAP). Urinary excretion of sodium (UNaV) and urine flow (UF) were significantly decreased during angiotensin II infusion. Intravenous injections of torasemide in the presence of angiotensin II caused a dose-dependent increase in UF, UNaV and urinary excretion of potassium (UKV), while a decrease in RVR was accompanied by an increase in RBF. UKV was greater in the furosemide group than in the torasemide group, despite both groups having the same degree of aquaresis and natriuresis. Continuous i.r.a. infusion of endothelin-1, 1·5 ng kg−1 min−1, produced effects similar to those of angiotensin II on renal haemodynamics; however, the onset of action was extremely slow compared with the effects produced by angiotensin II. Endothelin-1 caused a significant decrease in UF, UNaV and UKV only at a later period, despite a relatively early depression of renal haemodynamics. Torasemide and furosemide also produced a sufficient diuretic action in this model. Overall, kaliuresis was greater in the furosemide group than in the torasemide group. The present study demonstrates that torasemide exhibited a significant diuretic action in the angiotensin II- or endothelin-1 -induced renal impairment model, with less kaliuresis than furosemide at a concentration which caused the same degree of natriuresis.
Comparative pharmacokinetics of tetrahydropyranyl-doxorubicin and doxorubicin in rat isolated lung
Authors: Dumas Monique , Dubuet Aleth , D'Athis Philippe , Camus Philippe , Escousse André
Published: April 2011

Rat isolated perfused lungs (Sprague-Dawley rats, n = 20) were studied to compare the pulmonary uptake of a new anthracycline, tetrahydropyranyl-doxorubicin (THP-DXR) with that of doxorubicin (DXR). Lung perfusions were initiated with a constituted medium containing either drug at concentrations of 1, 10 or 100 μm. Lungs were perfused by recirculation for 60 min. Thirteen perfusate samples were collected over 60 min and subjected to HPLC for assay. The perfusate concentration of THP-DXR decreased to 24 ± 5% of the initial concentration and to 8 ± 2%, 20 and 60 min after the beginning of the infusion, respectively. Corresponding values for DXR were 77 ± 16 and 52 ± 15%, respectively (P < 0·05). During the THP-DXR perfusion, the area under the perfusate concentration vs time curve (AUC) was decreased to one-third and the clearance was increased 3-fold (P < 0·05). The pulmonary concentration of THP-DXR reached 0·032 ± 0·01 μmol g−1 60 min after the beginning of a perfusion of 1 μm of the drug. This concentration increased to 0·379 ± 0·11 μmol g−1 when the initial dose concentration was 10 μm. Corresponding lung concentrations for DXR were 0·013 ± 0·001 and 0·150 ± 0·04 μmol g−1, respectively (P < 0·05). The perfusate concentration/initial concentration ratio decreased by the same amount whether a 1 or 10 μm initial concentration of either drug was used. An initial concentration of 100 μm of THP-DXR, unlike DXR, consistently induced oedema in the perfused lung. No metabolite of either drug was revealed during the course of our study. These findings suggest: (1) a higher lung affinity for THP-DXR; (2) a correlation between lung uptake and dose consistent with a passive diffusion transport mechanism for both drugs; (3) a higher acute toxicity induced by THP-DXR; (4) the absence of metabolic activity in the lung with regards to both anthracyclines.
Evaluation of starch obtained from Ensete ventricosum as a binder and disintegrant for compressed tablets
Authors: Gebre-Mariam Tsige , Nikolayev Alexander S
Published: April 2011

The binding and disintegrant properties of starch obtained from Ensete ventricosum Musaceae have been evaluated. The effect of the starch on the physical properties such as crushing strength, friability and disintegration time of tablets of chloroquine phosphate, dipyrone and paracetamol was compared with tablets prepared with potato starch. The results show that enset starch can be used both as a tablet binder and disintegrant and the indication is that enset starch has a better binding ability and less disintegrating power than potato starch.
Microspheres of Human Serum Albumin with Barbiturates: Effect of Drug Partition Coefficient on Preparation and Drug Release
Authors: Filipović-Grĉić J , Jalsšenjak I
Published: April 2011

Human serum albumin microspheres were prepared with a series of barbiturates by the thermal denaturation method. The barbiturates were of similar general physicochemical properties but different partition coefficients. The total drug content of microspheres was dependent on the partition coefficient, and an increase in the partition coefficient caused a decrease in the drug content of finished microspheres due to drug migration to the outer organic phase during preparation. The ensemble drug release from microspheres was followed by the paddle method and by potentiometric titration with a pH-stat. Nonlinear regression analysis showed the best fit for the spherical Higuchi equation, especially first-order kinetics (bi-phasic). The drug partition coefficient affected the release in such a way that drugs with higher partition coefficients were released faster and to a greater extent than those with lower coefficients.
Effects of Cromakalim (BRL 34915) in Trachea Isolated from Actively Sensitized Guinea-pigs
Authors: Cortijo J , Pedrós C , Ortiz J L , Morcillo E J
Published: April 2011

The effects of cromakalim were examined in tracheal strips isolated from normal (unsensitized) guinea-pigs and from animals actively sensitized to bovine serum albumin. Sensitized tracheae exhibited hyper-responsiveness to KCl, acetylcholine and histamine. In normal and sensitized tracheae, cromakalim (0·01–10 μm) produced a concentration-related suppression of spontaneous tone. The ability of cromakalim to relax tracheal strips was reduced when tone was raised by KCl (25 Mm), acetylcholine (0·1 Mm) or histamine (0·1 Mm) and lost against KCl (120 Mm)-induced spasm. Procaine (5 Mm) abolished the relaxant effect of cromakalim whilst tetraethylammonium (8 Mm) was without effect. These effects were similar in normal and sensitized tissues. Cromakalim (10 μm) produced minor alterations of the concentration-effect curves of KCl (1–100 Mm), acetylcholine (1 Nm–1 Mm) and histamine (1 Nm–1 Mm) in normal and sensitized tissues. The results from this pharmacomechanical study do not support the hypothesis that altered properties of cromakalim-sensitive K+ channels underlie the airway hyper-reactivity induced by active sensitization to bovine serum albumin.
Effect of metadoxine on striatal dopamine levels in C57 Black mice
Authors: Fornai Francesco , Alessandri Maria Grazia , Bonuccelli Ubaldo , Scalori Vera , Corsini Giovanni U
Published: April 2011

In the present study, we examined the effect of metadoxine on striatal levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in male C57 Black mice. Striatal content was assayed after systemic administration of metadoxine ranging from 1 μg kg−1 to 500 mg kg−1. Striatal dopamine increased 1 h after treatment with metadoxine (150 mg kg−1), but the most notable effect was obtained 24 h after the drug administration. At this time a plateau was reached; the two major metabolites of dopamine showed the same trend. Seven days after metadoxine administration, striatal dopamine approached the control values. Over the same time intervals, striatal 5-HT increased to a lesser extent and 5-hydroxy-indoleacetic acid did not differ significantly from controls. Striatal dopamine increased significantly at a dose of 250 μg kg−1 up to a dose of 1 mg kg−1 metadoxine; no further increment was observed between 1 and 500 mg kg−1 metadoxine. Administration of each component at doses equimolar to 1 mg metadoxine showed that pyridoxine produced only a mild increase in striatal dopamine compared with controls. We suggest that the metadoxine-induced striatal dopamine increase is obtained by increasing synthesis of dopamine.
Biocompatibility of Wound Management Products: A Study of the Effects of Various Polysaccharides on Murine L929 Fibroblast Proliferation and Macrophage Respiratory Burst
Authors: Schmidt Richard J , Chung Lip Yong , Andrews Andrea M , Spyratou Olga , Turner Terence D
Published: April 2011

An in-vitro screening method to examine the biocompatibility of materials used in wound management has been evaluated. This involved the use of a macrophage respiratory-burst assay and a fibroblast proliferation assay to represent respectively the inflammatory and the granulation phases in wound healing. Standard polysaccharides (calcium and sodium alginates, ŗ-carrageenan, chitin, chitosan lactate, chondroitin sulphate and pectic acid) were used as test compounds. None of the polysaccharide samples caused a significant increase in L929 fibroblast cell numbers relative to control after 6 days incubation. The overall effect of exposure of the fibroblast cultures to the alginates, carrageenan and chondroitin sulphate was an extension of lag phase followed by an enhanced rate of cell proliferation in the logarithmic phase. Only calcium and sodium alginates and chondroitin sulphate enhanced the respiratory burst activity of murine macrophages; ŗ-carrageenan and chitosan lactate were markedly inhibitory. The results suggest that a macrophage activity assay should be included as part of an in-vitro screening program to evaluate the biocompatibility of wound management materials and to detect intrinsic biological activity.
Anti-inflammatory activities of Emblica officinalis Gaertn leaf extracts
Authors: Asmawi M Z , Kankaanranta H , Moilanen E , Vapaatalo H
Published: April 2011

Emblica officinalis Gaertn, a tree growing in subtropical and tropical parts of China, India, Indonesia and the Malay Peninsula, has been used for anti-inflammatory and antipyretic treatments of rural populations in these areas. In the present study, we examined the effects of Emblica officinalis extracts on carrageenan- and dextran-induced rat hind paw oedema. Anti-inflammatory activity was found in the water fraction of methanol extract of the plant leaves. The effects of the same fraction were tested on the synthesis of mediators of inflammation such as leukotriene B4 (LTB4), platelet-activating factor (PAF) and thromboxane B2 (TXB2), and on LTB4- and N-formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-induced migration of human polymorphonuclear leucocytes (PMNs) in-vitro. The water fraction of the methanol extract inhibited migration of human PMNs in relatively low concentrations. It did not inhibit LTB4 or PAF synthesis in human PMNs or TXB2 synthesis in human platelets during clotting, suggesting that the mechanism of the anti-inflammatory action found in the rat paw model does not involve inhibition of the synthesis of the measured lipid mediators.
Prazosin-induced Blockade of Extraneuronal Uptake Facilitates Dopaminergic Modulation of Muscle Twitches in Rat Vas Deferens
Authors: Elmallah Ahmed I , Sharabi Fouad , Omar Amal G , El-Mas Mahmoud M
Published: April 2011

Preliminary findings in our laboratory have shown that prazosin augmented the inhibitory effects of dopamine on the electrically-evoked muscle twitches in rat vas deferens. In this study, we opted to investigate the underlying mechanism and whether a prazosin-induced blockade of extraneuronal uptake process may be involved.

Cumulative additions of dopamine (1.8 times 10−7-4.4 times 10−5m) elicited slight (<30%) but dose-related inhibition of electrically-evoked (0.05 Hz, 1 ms duration and supramaximal voltage) muscle twitches of the vas deferens. Pretreatment with cocaine (10 μm), prazosin (50 nm) or oestradiol (10 μm) produced comparable potentiation of the inhibitory responses of dopamine; the pD2 values to dopamine amounted to 4.47 ± 0.20, 4.72 ± 0.21 and 4.56 ± 0.19, respectively. A lower concentration of prazosin (5 nm) failed to alter dopaminergic responses. Further potentiation of dopamine responses was demonstrated in tissues preincubated with a combination of cocaine plus prazosin (50 nm), or cocaine plus oestradiol (pD2, 5.40 ± 0.11 and 5.42 . 0.05, respectively). However, a mixture of all three drugs failed to elicit any further increase in dopamine responses, a finding that may suggest an extraneuronal uptake blocking activity for prazosin. Inhibition of muscle twitches evoked by bromocriptine, a dopaminoceptor agonist which is not a substrate for extraneuronal uptake, was not affected by prazosin (50 nm) pretreatment.

The findings presented in this study emphasize the role of dopamine in modulating noradrenergic neurotransmission in rat vas deferens. More importantly, the results suggest that prazosin may act to block the extraneuronal uptake at noradrenergic sites, an effect that may account for its capability to facilitate dopaminergic modulation of noradrenergic neurotransmission.
Availability and Mean Transit Times of Phenol and Its Metabolites in the Isolated Perfused Rat Liver: Normal and Retrograde Studies Using Tracer Concentrations of Phenol
Authors: Ballinger Linsay N , Cross Sheree E , Roberts Michael S
Published: April 2011

Phenolic compounds are frequently detoxified by the formation of sulphate and glucuronic acid conjugates in the liver. These conjugates are formed in the hepatocytes and then either transported into the bile or back into the blood. In this study, we examined the transport kinetics of phenol and its metabolites in the isolated perfused rat liver by monitoring the outflow profiles of these compounds after a bolus input in a single pass preparation.

Phenol was almost exclusively metabolized to phenyl sulphate (97%) at the trace concentrations used, with the amount of phenol and metabolites excreted into the bile being minimal (3.5%). The metabolite formed was rapidly transported back into the perfusate, with mean transit times of 17.4 and 12.3 s anterograde and 24.9 and 24.2 s retrograde at flow rates of 15 and 30 mL min−1 respectively, which were intermediate between those of Evans blue and water. The outflow concentration-time profile for phenyl sulphate formation was unaffected by the addition of another organic anion (bromosulphophthalein).

The effect of enzyme zonation on outflow concentration-time profiles was also investigated using retrograde perfusions. The transit time ratios for generated metabolite to water for anterograde perfusions (0.6) was found to be more than twice that for retrograde perfusions (0.23) at 15mL min−1 and approximately 1.6 times greater at 30mL min−1, being 0.58 and 0.37 respectively. The relative ratios obtained are consistent with previous findings that normalized variance of solutes in the retrograde perfusions is greater than that for anterograde perfusions.
Frusemide and Its Acyl Glucuronide Show a Short and Long Phase in Elimination Kinetics and Pharmacodynamic Effect in Man
Authors: Vree Tom B , Van Den Biggelaar-Martea Magdalena , Verwey-Van Wissen Corrien P W G M
Published: April 2011

The pharmacokinetics of 80 mg frusemide given orally were investigated in normal subjects using a direct HPLC method for parent drug and its acyl glucuronide conjugate.

Two half-lives could be distinguished in the plasma elimination of both frusemide and its conjugate, with values of 1.25 ± 0.75 and 30.4 ± 11.5 h for frusemide and 1.31 ± 0.60 and 33.2 ± 28.0 h for the conjugate. The renal excretion rate-time profile showed two phases; the rapid elimination phase lasted from 0–15 h and the second and slow phase, from 15–96 h. During the first 15 h, 33.3 ± 4.8% of the dosed frusemide was excreted; in the remaining period 15–96 h, 4.6 ± 1.5% was excreted. In the same two periods the excretion of the glucuronide was 13.4 ± 4.7 and 1.9 ± 1.1%, respectively. The mean renal clearance of frusemide was 90.2 ± 16.9 mL min−1 during the first period and 91.5 ± 29.3 mL min−1 in the remaining period, during which the stimulation of urine production was absent. The renal clearance of the acyl glucuronide was 702 ± 221 mL min−1 in the first period, but only 109 ± 51.0 mL min−1 in the second period. The stimulated urine production in the first 6 h after administration amounted to 2260 ± 755 mL (measured urine production minus baseline value of 1 mL min−1 (360 mL). During the second or rebound period (6–96 h after drug administration), the quantity of urine was 990 ± 294 mL lower than what would have been expected from the baseline production of 5400 mL. This reduced production (0.82 mL min−1) is equivalent to an 18% reduction in the average urine flow rate of 1 mL min−1.
Effects of Clonidine Pretreatment on the Local Anaesthetic Activity of Bupivacaine in Mice
Authors: Attolini Laurence , Gantenbein Manon , Grignon Sylvain , Bruguerolle Bernard
Published: April 2011

This study was designed to document possible changes in bupivacaine local anaesthetic activity in mice after a single injection of clonidine (0.1 or 1 mgkg−1, i.p.). The local anaesthetic activity was evaluated during 60 min, according to a previously reported technique, using sciatic nerve blockade by injection of bupivacaine in the area of the sciatic nerve.

Clonidine pretreatment modified the local anaesthetic activity of bupivacaine dose-dependently. The time of recovery was higher for clonidine-pretreated mice (40.00±7.24 min, 0.1 mgkg−1 clonidine: 50.0±9.35 min, 1 mgkg−1 clonidine) compared with controls (27.22±1.21 min, P = 0.02). The maximal effect (Emax) was significantly lower for the pretreated group (1.15±0.13 units, 0.1 mgkg−1; 1.35±0.09 units, 1 mgkg−1) compared with the control group (1.72±0.13, P = 0.01).

Our data indicate a significant decrease in the duration of anaesthetic activity of bupivacaine in clonidine-pretreated mice.
Cardiovascular Effects of NT-1, a New Patch Form of Nitroglycerin, Alone and in Combination with Nifedipine in Conscious Dogs
Authors: Kanda Atsuhiro , Yoshida Masumi , Kanou Mayumi , Yamaguchi Kazumasa , Kyuki Kohei
Published: April 2011

The cardiovascular effects of NT-1, a new patch form of nitroglycerin, alone and in combination with nifedipine in conscious dogs were examined.

NT-1 (2.5mgkg−1 nitroglycerin) decreased systolic blood pressure by 10–15%, while diastolic blood pressure and heart rate were not affected. Coronary blood flow and calculated rate-pressure product were decreased. These parameter changes occurred at 30 min after NT-1 application and remained constant for 8 h until NT-1 was removed. After administration of NT-1 in combination with nifedipine, systolic blood pressure was significantly decreased to a greater extent, and heart rate and coronary blood flow showed a tendency to increase compared with nifedipine alone. Rate-pressure product was not changed compared with that obtained on administration of nifedipine alone.

These results suggest that NT-1 may be applicable as a transdermal sustained release medication, and show that in combination with nifedipine, NT-1 can induce a large increase in coronary blood flow without further increasing rate-pressure product.
Absorption of Phenol Red and Bromphenol Blue as Model Drugs from the Peritoneal Cavity around the Liver Surface in Rats
Authors: Nishida Koyo , Amagishi Hiroaki , Sasaki Hitoshi , Nakamura Junzo
Published: April 2011

The importance of the injection site on the pharmacokinetics of phenol red and bromphenol blue as model drugs after intraperitoneal administration into rat was examined.

Their absorption rate from the peritoneal cavity was faster after intraperitoneal administration to the liver surface than that after intraperitoneal administration to the distal small intestine, as shown by the increase in maximum concentration and decrease in mean residence time in plasma. A similar tendency was observed in the biliary excretion pattern. The enhanced absorption rate was supported by the significantly smaller amount of both drugs remaining in the peritoneal cavity at 15 min after liver surface administration than that after small intestine administration. The liver concentration of the model drugs at 15 min after liver surface administration was 1.5–2.0 times that after small intestine administration.

Accordingly, liver surface administration was shown to be effective with good absorption and efficient drug delivery to the liver.
The Factors that Influence Skin Penetration of Solutes
Authors: Abraham Michael H , Chadha Harpreet S , Mitchell Robert C
Published: April 2011

In this study, human skin permeation data are analysed using a number of physicochemical descriptors.

It is shown that the equilibrium distribution of compounds between the stratum corneum and water (log Km) can be correlated with either water-octanol partition coefficients (log Poct) or Abraham solute descriptors. The latter reveals that partitioning of compounds is governed by solute size and hydrogen-bond acidity that favour the stratum corneum, and solute dipolarity/polarizability, and hydrogen-bond basicity that favour water.

For water-skin permeation coefficient (log kp) data it is demonstrated that log Poct cannot be used as a descriptor across a wide range of chemical families, but that log kp can be correlated using Abraham solute descriptors. These disclose that log kp values are increased by solute size and decreased by solute dipolarity/polarizability, hydrogen-bond acidity and hydrogen-bond basicity. It is suggested that different solutes travel through the stratum corneum by the same route, which cannot be distinguished as an intercellular or transcellular mechanism.

Backward skin permeation is examined and it is demonstrated that factors governing this process can be rationalized. Furthermore, it is shown that using the Abraham analysis, log Poct can be corrected to correlate log kp over a wide range of compounds.

The determination of solute descriptors is also described, indicating that Abraham solute descriptors can be obtained by substructure summation and partition coefficient measurements, so that dermatological properties can be predicted for solutes without the necessity for synthesis.
An Attempt to Clarify the Mechanism of the Penetration Enhancing Effects of Lipophilic Vehicles with Differential Scanning Calorimetry (DSC)
Authors: Leopold Claudia S , Lippold Bernhard C
Published: April 2011

In a previous in-vivo skin penetration study, it was observed that certain lipophilic liquid vehicles enhanced drug penetration, whilst others did not.

To clarify the mechanism of skin penetration enhancement, isolated sheets of human stratum corneum were measured by differential scanning calorimetry (DSC), either untreated or after pretreatment with various lipophilic liquids (highly purified light mineral oil, isopropyl myristate, caprylic/capric acid triglycerides containing 5% phospholipids, dibutyl adipate, dimethicone 100, cetearyl iso-octanoate, caprylic/capric acid triglycerides), commonly used in ointment bases.

All samples were analysed over a heating range of at least — 10–130°C. All DSC curves were evaluated with regard to the phase-transition enthalpies (peak areas) and peak maximum temperatures of the lipid-phase transitions at ca 75 and 85°C.

With the exception of dimethicone 100, cetearyl iso-octanoate and caprylic/capric acid triglycerides, all vehicles showed characteristic alterations of the phase-transition temperatures and enthalpies of the stratum corneum lipids. Mineral oil and isopropyl myristate caused a reduction of the enthalpy and a decrease of the phase-transition temperatures. These two vehicles are thought to fluidize the lamellar-gel phase of the stratum corneum lipids, and possibly partially dissolve the lipids. Dibutyl adipate and caprylic/capric acid triglycerides containing 5% phospholipids decreased the phase-transition enthalpy only, probably due to dissolution or extraction of the stratum corneum lipids.

These DSC results provide an explanation for the in-vivo penetration-enhancing effects observed previously.
Pharmacokinetic Properties and Interactions with Blood Components of N4-Hexadecyl-1-β-d-arabinofuranosylcytosine (NHAC) Incorporated into Liposomes
Authors: Horber D H , Ottiger C , Schott H , Schwendener R A
Published: April 2011

N 4-Hexadecyl-1-β-d-arabinofuranosylcytosine (NHAC) is a new lipophilic derivative of 1-β-d-arabino-furanosylcytosine (ara-C) with strong antitumour activity. The interactions of NHAC incorporated into small unilamellar liposomes of different compositions with blood components were evaluated.

In comparison with ara-C, NHAC is highly protected against deamination to inactive arabinofurano-syluracil (ara-U) in human plasma, resulting in only 2% conversion into ara-U after 4 h incubation at 37°C, whereas from ara-C more than 80% was deaminated. In in-vitro incubations with human blood, it was found that NHAC was transferred from the liposomes at about 47% efficiency to plasma proteins, particularly to albumin and to the high and low density lipoproteins. The remaining part of NHAC was bound to erythrocytes (50%) and to leucocytes (3%). The addition of poly(ethylene) glycol-modified phospholipids to the liposomes (PEG liposomes), which were composed of soy phosphatidylcholine and cholesterol (plain liposomes), did not significantly prevent the fast transfer of NHAC from the liposomes to the blood components. Pharmacokinetic studies in mice revealed that NHAC had biphasic kinetics in blood with a t 1/2α of 16 min and a 1/2β of 3·8 h when the drug was formulated in plain liposomes and a t 1/2α of 15 min and a t 1/2β of 9·67 h in PEG liposomes, respectively. NHAC was predominantly distributed in the liver with 29% of the injected dose found after 30 min. However, no accumulation occurred in the liver and NHAC was eliminated with biphasic kinetics resulting in a t 1/2α of 53 min and a t 1/2β of 11·8 h. In spleen, kidney and bone marrow the levels of NHAC remained low.

In summary, NHAC is highly resistant against deamination and rapidly transferred from the liposomes to the blood components, independently of the liposome compositions tested.
The Effects of Racemic, (+)- and (-)-Pinacidil on the Membrane Potential of the Rat Aorta
Authors: Doggrell Sheila A , Bishop B E , Barnett Carolyn W
Published: April 2011

The endothelium-intact and -denuded rat aorta is hyperpolarized by racemic and (-)-pinacidil, probably by opening ATP-dependent potassium channels. (+)-Pinacidil caused depolarization of the endothelium-intact and -denuded rat aorta.

The depolarization induced by 20 mm KC1 in the endothelium-intact rat aorta was reversed by racemic and (-)-, but not by (+)-pinacidil. On the endothelium-intact rat aorta, isoprenaline produced hyperpolarization and ICI 118 551 (erythro-(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) had no effect alone but prevented isoprenaline from causing hyperpolarization. The hyperpolarization induced by isoprenaline was reversed by racemic and (+)-, but not by (-)-pinacidil. Glibenclamide depolarized the endothelium-intact rat aorta and prevented the hyperpolarizing action of racemic pinacidil and (-)-pinacidil. (+)-Pinacidil prevented the hyperpolarizing action of (-)-pinacidil. Glibenclamide is probably preventing the hyperpolarization associated with opening of the ATP-dependent potassium channel by blocking this channel.

Several mechanisms may underlie the depolarizing action of (+)-pinacidil, including blocking of ATP-dependent potassium channels.
High-performance Liquid Chromatographic Determination of Trazodone and 1-m-Chlorophenylpiperazine with Ultraviolet and Electrochemical Detector
Authors: Ohkubo Tadashi , Osanai Takako , Sugawara Kazunobu , Ishida Masayuki , Otani Koichi , Mihara Kazuo , Yasui Norio
Published: April 2011

A high-performance liquid chromatographic (HPLC) assay was developed for the determination of trazodone and its metabolite, 1-m-chlorophenylpiperazine (m-CPP), in plasma.

The high level of trazodone in plasma was detected by ultraviolet absorbance at 254 nm and the low level of m-CPP in plasma was detected by coulometric electrochemical detection at 840 mV on the series arrangement of two detectors. Pilsicainide as an internal standard for both compounds was monitored by both detectors. Trazodone and m-CPP in plasma were extracted by a rapid and simple procedure based on CN bonded-phase extraction, and C8 reversed-phase HPLC separation.

Determination was possible for trazodone in the concentration range 100–2000 ng mL−1 and for m-CPP in the concentration range 5–100 ng mL−1. The recoveries of trazodone and m-CPP added to plasma were 81·0–84·2 and 68·0–73·2%, respectively, with coefficients of variation of less than 7·3 and 8·2%, respectively. The method is applicable to high level monitoring of trazodone and low level monitoring of m-CPP in plasma of healthy volunteers and patients treated with trazodone.
Effects of Ageing on the Oral Absorption of D-Xylose in Rats
Authors: Yuasa Hiroaki , Kawanishi Koji , Watanabe Jun
Published: April 2011

The effects of ageing on the oral absorption of d-xylose were investigated in rats.

The pharmacokinetic analysis of d-xylose concentration in plasma after oral administration showed that the fraction absorbed was increased to 0·998 ± 0·002 and 0·950 ± 0·049, respectively, in old (52 weeks) and very old (102 weeks) rats, compared with 0·768 ± 0·052 in young (9 weeks) rats, while the absorption rate constant was not significantly changed: 0·944 ± 0·233, 0·844 ± 0·143 and 0·725 ± 0·004 h−1, respectively, in young, old and very old rats. The absorbed fractions estimated from faecal and urinary excretion were in agreement with those by the pharmacokinetic analysis. Thus, the present study demonstrated an increase in the extent of the oral absorption of d-xylose with ageing. The increase in the extent of absorption might be caused by a delay in the intestinal transit, because the absorption rate constant was unchanged.

These results suggest potential increases with ageing in the fractions absorbed of hydrophilic drugs such as d-xylose where oral absorption is incomplete.
Acute Moderate Hypoxia in Conscious Rabbits: Effect on Hepatic Cytochrome P450 and on Reactive Oxygen Species
Authors: Proulx Mario , Du Souich Patrick
Published: April 2011

This study aimed to document whether acute moderate hypoxia modifies the amount and activity of hepatic cytochrome P450 and in addition, induces changes in the production or the ability to neutralize oxygen reactive species (ORS).

Rabbits were exposed to a low partial pressure of oxygen (12%) for 8 or 24 h, killed, and the amount and activity of cytochrome P450, lipid peroxidation, microsomal chemiluminescence and enzymatic scavenger activity were assessed in the liver. After 8 h of hypoxia, total amount but not the activity of cytochrome P450 was decreased, although after 24 h of hypoxia, both the amount and the activity of cytochrome P450 were decreased. Hypoxia for 8 h increased the activity of glutathione peroxidase. However, after 24 h of hypoxia, lipid peroxidation, microsomal chemiluminescence and superoxide dismutase activity were increased, while hepatic glutathione and glutathione peroxidase activity were reduced, modifications that suggest an enhanced presence of ORS. In in-vitro studies, an ORS generating system reduced the activity of cytochrome P450 and enhanced lipid peroxidation of hepatic microsomal membranes, supporting the view that ORS can impair cytochrome P450.

The results of the present study show that hypoxia induces changes in the amount and activity of cytochrome P450, as well as in the production or the ability to neutralize ORS, and that these changes are time-dependent.
The Effects of Danshen (Salvia miltiorrhiza) on Warfarin Pharmacodynamics and Pharmacokinetics of Warfarin Enantiomers in Rats
Authors: Chan K , Lo A C T , Yeung J H K , Woo K S
Published: April 2011

The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats.

After a single oral dose of racemic warfarin (2 mg kg−1), treatment with oral Danshen extract (5 g kg−1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0·2 mg kg−1 day−1 for 5 days) the 3-day treatment of Danshen extract (5 g kg−1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin.

The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.
Brain Distribution Characteristics of Xanthine Derivatives and Relation to their Locomotor Activity in Mice
Authors: Haghgoo Soheila , Hasegawa Takaaki , Nadai Masayuki , Wang Li , Ishigaki Takeo , Miyamoto Ken-Ichi , Nabeshima Toshitaka
Published: April 2011

The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined.

When these xanthines were administered orally, enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg−1, MPX caused a decrease in such activity over 10 mg kg−1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > enprofylline. The inhibition constants (Ki) for adenosine A1 receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, > 1000 and 112, 26·4 and 49, and > 1000 and 111 μm for theophylline, enprofylline, MPX, and oxpentifylline, respectively.

These findings suggest that the lack of effects of enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A1 affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.