bluuebunny/crossref_metadata_2025 huggingface dataset:
Interspecies Differences and Scaling for the Pharmacokinetics of Xanthine Derivatives
Authors: Tsunekawa Yoshimi , Hasegawa Takaaki , Nadai Masayuki , Takagi Kenzo , Nabeshima Toshitaka
Published: April 2011

Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1-methyl-3-propylxanthine (MPX), were investigated in mice, rats, guinea-pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model-independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non-renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals.
Atrial natriuretic peptide inhibits the spontaneous contractions of rabbit isolated ileum
Authors: Blandizzi C , Agen C , Natale G , Del Tacca M
Published: April 2011

The present study investigates the effects of atriopeptin II on spontaneous phasic contractions of rabbit isolated ileum. Atriopeptin II caused a significant and concentration-dependent decrease in ileum motor activity. This effect was mimicked by 8-Br-cGMP and it was not affected by pretreatment with tetrodotoxin. Verapamil significantly decreased ileum contractions; however, in the presence of this calcium blocker, atriopeptin II further reduced ileal motility. These findings demonstrate that atriopeptin II depresses the motility of rabbit ileum through a cGMP-dependent mechanism and suggest that neither ileal neural networks nor extracellular calcium are involved in this effect.
Disposition of asarone after intravenous administration to rabbits assessed using HPLC
Authors: Tsai T H , Chen C M , Chen C-F
Published: April 2011

A simple and sensitive high-performance liquid chromatography (HPLC) method for the determination of asarone in rabbit plasma has been developed. Up to 0·1 mL of plasma containing asarone was deproteinated by acetonitrile, which contained an internal standard (indomethacin). The supernatant was injected into a Nucleosil 7C18 column using acetonitrile-water-triethylamine (55:45:0·1 v/v, pH 5·4–5·5, adjusted with orthophosphoric acid) as the mobile phase and UV detection at 257 nm, followed by UV spectrum identification (between 200 and 380 nm) with a photodiode array detector. The method is rapid, easily reproduced, selective and sensitive. It was applied to pharmacokinetic studies of asarone in rabbit, after 5, 10, or 20 mg kg−1 intravenous administration. Rapid distribution followed by a slower elimination phase was observed from the plasma concentration–time curve. The plasma disposition at each dose fitted well to a two-compartment open model and the terminal disposition became much slower as the dose was increased, suggesting a nonlinear dose-dependent plasma asarone disposition.
Transfer of Heparin Across the Human Perfused Placental Lobule
Authors: Bajoria Rekha , Contractor Soli F
Published: April 2011

A system of dual perfusion of an isolated lobule of term human placenta was used as a model to study the transfer of heparin from maternal to foetal circulation. The metabolic viability of the system was assessed by measuring β-HCG and alkaline phosphatase levels in both maternal and foetal perfusates. Creatinine and antipyrine were used as markers to determine juxtaposition of the maternal and foetal circulations. Results of this study indicate that following administration of a single bolus dose of heparin into the maternal circulation, its concentration declined slowly from 99·01 ±2·98 at 15 min to 97·23 ±4·12% and transfer of heparin in the foetal circulation was linear and increased from 0·10% ±0·05% at 15 min to 0·46 ±0·19% over a period of 120 min. The maternal (MAUC) and foetal (FAUC) concentration-time integrals were found to be 70160 ± 1332 and 340 ± 30 int. units min mL−1, respectively. Placental permeability of heparin and creatinine, calculated as the ratio of foetal concentration to the integral maternal–foetal concentration difference, was 8·65 × 10−5 ± 0·80 × 10−5 and 0·033 ±0006 mL min−1 g−1 of perfused placental weight, respectively. These data suggest that heparin was transferred from the maternal to the foetal circulation in small quantities.
Semicarbazide-sensitive Amine Oxidase from the Smooth Muscles of Dog Aorta and Trachea: Activation by the MAO-A Inhibitor Clorgyline
Authors: Yu Peter H , Fang Chiung-Yao , Yang Chuen-Mao
Published: April 2011

Semicarbazide-sensitive amine oxidase (SSAO) has been identified in the dog trachea and aorta smooth muscles. The dog SSAO is blocked by hydrazine inhibitors. SSAOs from several different vascular smooth muscle sources, such as the rat and bovine aorta, and human umbilical artery, as well as the bovine plasma, are insensitive to the MAO-A inhibitor clorgyline; the dog SSAO on the other hand is significantly activated by clorgyline. Two methods, i.e. radioenzymatic and fluoroemetric methods, have been applied to substantiate this clorgyline-induced activation. The activation was detected with respect to the deamination of different substrates, such as benzylamine, β-phenylethylamine and longer carbon chain aliphatic amines, but not with respect to methylamine. The clorgyline effect is reversible, non-competitive and time-independent; it depends on electrostatic and hydrophobic interactions between clorgyline and hydrophobic regions of the dog SSAO enzyme.
Contractile Responses of Chicken Rectum to Stimulation of Remak's Nerve or Purinoceptors: Effect of Suramin
Authors: Bartlet A L
Published: April 2011

Stimulation of Remak's nerve produced a rapid contraction of the rectal muscle which was resistant to blockade by hyoscine, followed by a slow contractile response which was cholinergic. With hyoscine (1 μm) in the Tyrode solution, the non-cholinergic contractile response to nerve stimulation was compared with the responses to adenosine triphosphate (ATP) and α,β-methylene adenosine triphosphate (α,β-Me ATP). In the presence of suramin (300 μm), the contractile response to ATP was increased by about 100%, whereas that to nerve stimulation was inhibited by approximately 17%. Suramin (60 μm) also discriminated between the contractile responses to ATP and nerve stimulation, only the former being potentiated by the drug. It seems probable that suramin potentiated the action of ATP in the rectum through inhibition of ectonucleotidase activity. If so, the potentiation should not extend to α,β-Me ATP, as this analogue of ATP is resistant to inactivation by the enzyme. Suramin inhibited the contractile response to α,β-Me ATP. Thus the neurotransmitter which mediated the hyoscine-resistant contractile response to stimulation of Remak's nerve was dissimilar to ATP, in that it was not potentiated by suramin and presumably was not inactivated by ectonucleotidase activity.
Fab-bound Colchicine Appears to Adopt Fab Fragment Disposition in Rats
Authors: Sabouraud Alain E , Urtizberea Michel , Benmoussa Kamel , Cano Nathalie J , Scherrmann Jean-Michel G
Published: April 2011

The disposition of colchicine-specific Fab fragments and the effect of Fab fragment administration on the disposition of colchicine were studied in anaesthetized bile duct-cannulated rats. One group of rats (n = 6) received a 125I-Fab dose of 38 mg kg−1 i.v. The plasma disposition was characterized by a volume of distribution of 179 ± 48 mL kg−1, total body clearance of 1·02 ±0·07 mL min−1 kg−1, t½α of 0·17 ± 0·03 h and t½α of 1·3 ± 0·3 h. Fab fragments were in part excreted by the renal route (15·6 ± 6% of the Fab dose), while biliary excretion was a minor route (< 2% of the Fab dose). Two other groups of rats received 15 μg kg−1 colchicine (n = 6) or 15 μg kg−1 colchicine plus 38 mg kg−1 colchicine-specific Fab fragments (n = 6) by intravenous infusion. Pharmacokinetics of colchicine was markedly altered in the Fab-colchicine-treated rats. In this group, distribution volume and total body clearance of colchicine were decreased by factors of 22 and 10, respectively, compared with the values in the colchicine-treated group and were very similar to those of Fab fragments. An 80% reduction of cumulative biliary excretion of colchicine was observed in Fab-colchicine-treated rats (P < 0·01). The fraction of colchicine dose excreted by the urinary route was 38 ± 6·9 and 9 ± 0·7% respectively in Fab-colchicine- and colchicine-treated groups (P < 0·01). These data show that during Fab treatment, colchicine followed the elimination kinetics of Fab fragments. This study supports the view that Fab fragments could be of benefit in acute colchicine poisoning by neutralizing colchicine in the vascular compartment and imposing its elimination kinetics on colchicine.
The Effect of Lipopolysaccharide on the Disposition of Xanthines in Rats
Authors: Wang Li , Hasegawa Takaaki , Nadai Masayuki , Muraoka Isao , Nabeshima Toshitaka , Kato Nobuo
Published: April 2011

The effect of lipopolysaccharide (LPS) isolated from Klebsiella pneumoniae O3 on the pharmacokinetic behaviour and metabolism of the xanthines, theophylline and 1-methyl-3-propylxanthine (MPX), which are mainly metabolized by the liver, was investigated in rats. LPS was infused at 0·25 mg kg−1 over a period of 20–30 min, 2 h before the administration of theophylline (10 mg kg−1) or MPX (2·5 mg kg−1). Concentrations of both xanthines in plasma and concentrations of the parent drug and metabolites in urine were measured by HPLC. Model-independent methods were applied to estimate the pharmacokinetic parameters for both xanthines. No significant changes in the pharmacokinetic parameters or metabolism of theophylline were observed in rats pretreated with LPS. However, the total body clearance and volume of distribution of MPX were significantly increased by pretreatments with LPS. Significant decreases in the binding capacity and number of binding sites on the albumin molecule were observed in the presence of LPS. Changes occurring in the protein binding behaviour as a result of the introduction of LPS is a primary factor which not only increases the volume of distribution but also increases total body clearance. These results indicate that LPS has no effect on the pharmacokinetics and metabolic pathway of theophylline although it changes the disposition of MPX due to decreases in the extent of the protein binding of MPX which is highly bound to protein.
Effect of Staurosporine Derivatives on Protein Kinase Activity and Vinblastine Accumulation in Mouse Leukaemia P388/ADR Cells
Authors: Miyamoto Ken-Ichi , Inoko Kohsei , Ikeda Kyoko , Wakusawa Shinya , Kajita Shinji , Hasegawa Takaaki , Takagi Kenzo , Koyama Masao
Published: April 2011

Inhibition by staurosporine derivatives of cyclic AMP-dependent protein kinase (A-kinase) and protein kinase C (C-kinase), and drug resistance has been investigated. The substitution of an acetyl or an ethoxycarbonyl group for the amine N-ethoxycarbonyl-7-oxostaurosporine moiety on the tetrahydropyran ring of staurosporine decreased inhibition of both protein kinases, but increased selectivity for C-kinase by further modification of the lactam moiety to the imide (NA-382). The activities of SF-2370 on protein kinases were decreased by decarboxylation and hydroxyalkylation. These staurosporine derivatives enhanced accumulation of vinblastine in adriamycin-resistant P388 (P388/ADR) cells in a dose-dependent manner. The potency for the drug accumulation of these compounds was correlated with their inhibitory activity on the drug efflux, but was not correlated with their activity on protein kinases. Staurosporine and NA-382, with high potency for vinblastine accumulation, inhibited the photolabelling of [3H]azidopine on 140 kDa P-glycoprotein in the plasma membrane. The tetrahydrofuran compounds and NA-357, which had low potency for the drug accumulation, hardly interacted with azidopine on P-glycoprotein. Most of these compounds were highly cytotoxic by themselves, and only NA-382 was less cytotoxic among them and completely reversed the vinblastine-resistance of P388/ADR cells at a non-cytotoxic concentration. These results suggest that staurosporine derivatives can enhance drug accumulation and inhibit drug resistance through their direct action on the P-glycoprotein.
Stimulation of Enterocyte Protein Kinase C by Laxatives In-vitro
Authors: Beubler Eckhard , Schirgi-Degen Andrea
Published: April 2011

To elucidate the role of protein kinase C in the mechanism of action of stimulatory laxatives, experiments were performed with preparations of rat lysed enterocytes. The phorbol ester 4-β-phorbol 12-myristate 13-acetate (PMA) concentration-dependently (2–200 μg mL−1) stimulated the activity of protein kinase C in this preparation. Ricinoleic acid, the active principle of castor oil, deacetylbisacodyl, the active principle of bisacodyl, and deoxycholic acid exerted the same effect, although less efficiently. This reflects their potency for inducing intestinal fluid secretion and prostaglandin release, effects that are also induced more potently by PMA. Accordingly, the potency of the three C18 fatty acids, ricinoleic acid, stearic acid and oleic acid on protein kinase C activity in-vitro, on prostaglandin E2 release and on net fluid secretion in-vivo runs in parallel. It is therefore concluded that stimulatory laxatives activate protein kinase C., leading to prostaglandin E2 release, thus resulting in net fluid secretion.
Sorption of isosorbide dinitrate to central venous catheters
Authors: De Muynck C , Vandenbossche G M R , Colardyn F , Remon J P
Published: April 2011

As several studies demonstrated the sorption of isosorbide dinitrate (ISDN) to intravenous delivery systems, a study on the sorption of ISDN to several central venous catheters was performed. Fourteen different catheters were perfused during a 2 h period, under simulated infusion conditions, with ISDN (250 μg mL−1) in 0·9% (w/v) sodium chloride. The drug loss to a polyethylene and a silicone catheter was 0·2 and 6·1%, respectively. The sorption to a polyvinylchloride heparin-coated thermodilution catheter was 1–6·9% depending on the length of the catheter. The drug loss to polyurethane catheters of different composition varied between 3·8 and 28·9%. For polyurethane catheters composed of cycloaliphatic polyurethanes an inverse relation was shown between Shore A hardness and sorption.
Measuring the Uptake of Azone into Excised Human Stratum Corneum from Thin Polymer Films
Authors: Schückler Fritz , Lee Geoffrey
Published: April 2011

The extent of uptake of Azone into excised human stratum corneum from thin polymer films has been measured using a sandwich model. With poly(dimethyl)siloxane, an Azone loading of the stratum corneum of 6–7% w/w was achieved. With Eudragit NE30D, a loading of less than 1% was reached. The extent of uptake into the stratum corneum and acceptor layers of the sandwich model depended on the Azone content of the films. The resulting enhanced uptake and flux of diazepam through the stratum corneum membrane into a polymeric acceptor layer corresponded closely to the amounts of Azone taken up and their known enhancing effects. The uptake of diazepam from the poly(dimethyl)siloxane films was ten times larger than that from Eudragit NE30D films. The extent of uptake is, therefore, controlled by the rate of release from the polymer and partitioning at the interface.
Dissimilarity in the mechanisms of action of KRN2391, nicorandil and cromakalim in canine renal artery
Authors: Kasai Hideo , Fukata Yuzo , Harada Katsuhiko , Fukushima Hideaki , Ogawa Nobuyuki
Published: April 2011

In the present study, we examined the mode of action of KRN2391 (N-cyano-N′-(2-nitroxyethyl)-3-pyridinecarboximida-mide monomethanesulphonate) in isolated canine renal artery compared with those of nicorandil and cromakalim. KRN2391 (10−8-3 × 10−5  m), nicorandil (10−7-3 × 10−4  m) and cromakalim (10−8-3 × 10−5  m) relaxed renal arteries contracted by 25 Mm KCl in a concentration-dependent manner. KRN2391-induced relaxation was inhibited by methylene blue (10−5  m) and glibenclamide (10−6  m). Nicorandil-induced relaxation was inhibited by methylene blue, but not by glibenclamide. The concentration-relaxation curve for cromakalim displayed a rightward parallel shift in the presence of glibenclamide. In the control observation, KRN2391 and nicorandil also produced full relaxation, but cromakalim did not. The present results suggest that KRN2391 acts as both a nitrate and a potassium channel opener, and nicorandil acts only as a nitrate and only in canine renal artery.
Percutaneous Permeation of Basic Compounds Through Shed Snake Skin as a Model Membrane
Authors: Takahashi Koichi , Tamagawa Satoko , Katagi Toyoshi , Rytting J Howard , Nishihata Toshiaki , Mizuno Nobuyasu
Published: April 2011

Relationships between the in-vitro permeability of basic compounds through shed snake skin as a suitable model membrane for human stratum corneum and their physicochemical properties were investigated. Compounds with low pKa values were selected to compare the permeabilities of non-ionized forms of the compounds. Steady-state penetration was achieved immediately without a lag time for all compounds. Flux rate and permeability coefficient were calculated from the steady-state penetration data and relationships between these parameters and the physicochemical properties were investigated. The results showed that permeability may be controlled by the lipophilicity and the molecular size of the compounds. Equations were developed to predict the permeability from the molecular weights and the partition coefficients of basic compounds.
Mechanisms of Action of Dopamine in the Peripheral Nervous System of Chicks and Rats
Authors: Lot Theodore Y
Published: April 2011

The effects and mechanisms of action of dopamine on the lower oesophagus and expansor secundariorum muscle (ESM) of chicks and on the bladder of rat have been examined. Dopamine contracted the lower oesophagus in a concentration-related fashion but failed to contract the muscle from chicks pretreated with reserpine or p-chlorophenylalanine. Contraction of the ESM by dopamine was antagonized by prazosin but not by propranolol. Supersensitivity of the ESM to dopamine observed 3 or 28 days after surgical denervation of the muscle was comparable. Dopamine did not exert any agonist effect on the rat bladder but depressed responses to stimulation of non-adrenergic, non-cholinergic (NANC) nerves in the bladder. These findings indicate that dopamine contracts the upper oesophagus of chicks by releasing 5-hydroxytryptamine, activates α-adrenergic receptors causing contraction of the ESM but depresses NANC neurotransmission in the bladder.
Comparison of the effects of loperamide and loperamide oxide on absorptive processes in rat small intestine
Authors: Hardcastle Jacqueline , Hardcastle P T , Goldhill J
Published: April 2011

Mucosal loperamide inhibited the absorption of glycine by everted sacs of rat small intestine over 10-, 30- or 60-min incubation periods, but loperamide oxide was without effect. In stripped intestinal sheets, loperamide inhibited the rise in short-circuit current associated with Na+-linked glucose absorption, but this effect was not observed with loperamide oxide. It is concluded that although there is evidence that loperamide oxide is converted to loperamide in the intestinal lumen, the rate at which free loperamide appears is not sufficient to inhibit absorptive processes.
Influence of a Bacterial Lipopolysaccharide on the Pharmacokinetics of Tobramycin in Rats
Authors: Nadai Masayuki , Hasegawa Tataaki , Kato Katsuyoshi , Wang Li , Nabeshima Toshitaka , Kato Nobuo
Published: April 2011

The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg−1) and inulin (100 mg kg−1) were administered intravenously 2 h after administration of 50,250 or 500 μg kg−1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 μg kg−1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.
Albumin microspheres as a drug delivery system for dexamethasone: pharmaceutical and pharmacokinetic aspects
Authors: Dilova Valia , Shishkova Valentina
Published: April 2011

Four types of albumin microspheres containing dexamethasone prepared by varying cross-linking time—30, 60, 120 and 180 min—were tested to examine the influence of heat cross-linking degree on the in-vitro drug release. Release rate of dexamethasone associated with the microspheres was slower for samples with a longer time of high temperature denaturation. Encapsulation in neat-stabilized albumin microspheres for 60 min at 100°C significantly retards the in-vivo release of dexamethasone and hence retards absorption from the injection site.
Subcutaneous Absorption Kinetics and Local Tissue Distribution of Interferon and Other Solutes
Authors: Cross Sheree E , Roberts Michael S
Published: April 2011

The subcutaneous absorption and consequent tissue distribution of interferon g was studied in an anaesthetized rat model. Interferon g showed a biphasic disappearance profile from a solution in a subcutaneous absorption cell. Both the initial rapid distribution phase and slower removal phase followed first order kinetics. The steady-state clearance of interferon g from the cell was 1·41 ± 0·38 × 10−3 mL min−1, and the absorption half-life (t½) was 3·8 ± 1·1 h (n = 4). Noradrenaline did not significantly alter either the clearance or absorption of interferon g (1·18 ± 0·44 × 10−3 mL min−1  P > 0·05, absorption t½ 4·96 ± 1·9 h, P > 0·05). Given that the clearance of smaller solutes, such as tritiated water, is significantly reduced when noradrenaline is coadministered, it is suggested that interferon g is removed via the lymphatic system rather than by the local blood supply. The amount of interferon g recovered in the plasma, urine and muscle is minimal relative to other solutes where the recovery is almost complete.
Renal Tubular Excretion of the N4-Acetyl Metabolites of Sulphasomidine and Sulphadimethoxine in the Dog
Authors: Boom Sandra P A , Wouterse Alfons C , Vree Tom B , Van Ginneken Cees A M , Russel Frans G M
Published: April 2011

To investigate whether dogs are able to excrete acetylated drugs by active transport, the plasma kinetics and renal excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine were studied in the beagle dog after a rapid intravenous bolus injection. Two doses of N4-acetylsulphasomidine (1050 and 105 mg) and one dose of N4-acetylsulphadimethoxine (472 mg) were administered on separate occasions. The renal clearance (CLR) was as follows: N4-acetylsulphasomidine (1050 mg) 34 mL min−1; N4-acetylsulphasomidine (105 mg) 28 mL min−1; and N4-acetylsulphadimethoxine (472 mg) 24 mL min−1. CLR was higher than expected on the basis of the measured glomerular filtration rate, indicating that the N4-acetyl metabolites may be excreted by the renal tubules by active tubular transport. Saturation of the excretion process of N4-acetylsulphasomidine occurred with a transport maximum of 930 ± 190 μg min−1 and a Michaelis-Menten constant of 37 ± 10 μg mL−1. It may be concluded that the dog renal organic anion transport system is able to secrete acetylated sulphonamides.
Characterization of the Analgesic Effects of Paracetamol and Caffeine Combinations in the Pain-induced Functional Impairment Model in the Rat
Authors: Granados-Soto Vinicio , López-Muñoz Francisco J , Castañeda-Hernández Gilberto , Salazar Luis A , Villarreal Julian E , Flores-Murrieta Francisco J
Published: April 2011

The analgesic activities of paracetamol (100, 178, 316 and 562 mg kg−1), caffeine (10,18, 32 and 56 mg kg−1) and combinations of these doses were tested on a pain-induced functional impairment model in the rat. Dysfunction of the right hind limb was induced by an intra-articular injection of 30% uric acid in the knee. Drugs were given orally and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol alone induced a dose-dependent analgesic effect whereas caffeine alone did not show any activity at the assayed doses. Combinations of 316 mg kg−1 paracetamol with either 10, 18, 32 or 56 mg kg−1 caffeine yielded analgesic effects significantly greater than that of paracetamol alone. The highest potentiation was observed with a paracetamol-caffeine mixture of 316–32 mg kg−1. Caffeine coadministration, however, did not significantly change paracetamol plasma levels. No potentiation was obtained with other combinations. Paracetamol plasma levels and analgesic effect observed with administration of 316 mg kg−1 paracetamol alone or 316–32 mg kg−1 of paracetamol-caffeine were fitted to the sigmoidal Emax model according to the Hill equation. The curves obtained were parallel, but that of the combination was shifted to the left. It is concluded that caffeine is able to potentiate the analgesic effect of paracetamol by a pharmacodynamic mechanism, but this only occurs at certain dose combinations.
New Pyrazolylhydrazone Derivatives as Inhibitors of Platelet Aggregation
Authors: Da Silveira Ivna Alana Freitas Brasileiro , Paulo Luiz Gonçalves , De Miranda Ana Luisa Palhares , Rocha Simone Oliveira , Freitas Antonio Carlos Carreira , Barreiro Eliezer Jesus
Published: April 2011

A series of 5-pyrazolylhydrazone derivatives was designed to be mixed hybrid isosteres of both BW755C and CBS-1108, which belong to the class of dual cyclo-oxygenase and 5-lipoxygenase inhibitors. Some derivatives of this series inhibit the in-vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5 μm), collagen (5 μg mL−1) and arachidonic acid (100 μm). The structure-activity relationships of this class of compounds were determined from these results. When ADP is used as the aggregation inducer, the presence of free oxygenated substituents at the p-position in the phenyl subunit of the hydrazone moiety favours inhibitory activity; p-methoxyformylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydrazone (100 μm), which has a methoxy group at this position was the most active with 62·8% inhibition of aggregation. In contrast, substitution in the aryl ring does not affect the aggregation induced by collagen, whereas the non-substituted compound, formylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydrazone, showed similar activity to those of substituted derivatives. In the arachidonic acid assays, the presence of an aryl ring linked to the hydrazone moiety, with an adequate electronic density at the ring due to the nature of its substitutents, is an important structural requirement for inhibitory activity.
Function of the SOS Process in Repair of DNA Damage Induced by Modern 4-Quinolones
Authors: Howard B M A , Pinney R J , Smith J T
Published: April 2011

The recA13 mutant of Escherichia coli strain K-12, which lacks recombination and SOS error-prone DNA repair is hypersensitive to nalidixic acid and to the newer 4-quinolones ciprofloxacin, norfloxacin and ofloxacin. However, whereas recombination-proficient but SOS repair-deficient strains, such as those carrying the lexA3 or recA430 alleles are no more sensitive to nalidixic than the lexA+  recA+ parent, they are more sensitive to the newer quinolones, although not as sensitive as the recA13 derivative. Nalidixic acid possesses only bactericidal mechanism A (which requires RNA and protein synthesis and is only effective on actively dividing cells), whereas the newer 4-quinolones exhibit additional mechanisms B (which does not require RNA and protein synthesis and is effective on bacteria unable to multiply) and C (which requires RNA and protein synthesis but does not depend on cell division). Results obtained with bacteria suspended in phosphate-buffered saline, which inhibits mechanism A, and with bacteria suspended in nutrient broth plus rifampicin, which inhibits mechanisms A and C, showed that the lexA3 mutant was still more sensitive than the lexA+ parent under these conditions. The results suggest that, unlike bactericidal mechanism A, DNA damage that results from bactericidal mechanisms B and C of the newer 4-quinolones is subject to SOS error-prone (mutagenic) repair.
K+ -Channel blockers and coronary vasoconstriction in guinea-pig perfused hearts in-vitro
Authors: Gwilt M , Orme J , Rourke J D , Henderson C G
Published: April 2011

Glibenclamide, glipizide and phentolamine, three drugs which have been reported to block ATP-dependent potassium channels, increased the coronary perfusion pressure in guinea-pig isolated hearts perfused at constant flow. Blockers of other types of potassium channels, 4-aminopyridine and UK-66,914, did not significantly increase perfusion pressure. Exposing hearts to a single concentration of 3 μm glibenclamide caused a greater degree of vasoconstriction than when this was preceded by lower concentrations. The 3 μm glibenclamide-induced vasoconstriction was reduced by prazosin(1 μm), mepyramine(0·1 μm) and ranitidine (10 μm) but not by a combination of mepyramine and ranitidine or by ritanserin (001 μm). These results suggest that a component of the vasoconstriction induced by glibenclamide may result indirectly from the release of vasoactive mediators.
Skin Wound Healing: Some Biochemical Parameters in Guinea-pig
Authors: Buffoni F , Banchelli G , Cambi S , Ignesti G , Pirisino R , Raimondi L , Vannelli G
Published: April 2011

Hairs were removed from the dorsal skin of guinea-pigs and 5–6 wounds (7 × 7 mm) were surgically induced by totally removing the epidermal and part of the dermal surface. They were then allowed to heal. The newly formed wound tissues were dissected at different times during the process and analysed by biochemical and histological methods. Hydroxyproline, proteins, DNA and semicarbazide-sensitive amine oxidase (SSAO) were measured, as were [14C]leucine and [3H]thymidine incorporation in some samples. The peroxidase-like activity of plasma albumin and the histology of wounds stained with haematoxylin-eosin were also studied. It was shown that SSAO enzymes, which are present in normal guinea-pig skin and have a high affinity for benzylamine are localized in fibroblasts. During skin healing in the newly formed tissue there was an increase in protein content which reached a maximum after 4–6 days; DNA content also increased. The rate of incorporation of [3H]thymidine and [14C]leucine paralleled DNA and protein content, respectively. The content of hydroxyproline had greatly decreased with respect to that in normal skin after 2–10 days. SSAO activity increased much less than DNA after 4 days whereas after 10–11 days it increased more than DNA, thus indicating that at this time it was probably produced by fibroblasts. No significant increase in the peroxidase-like activity of albumin was observed 4, 8 or 11 days after surgery. Treatment of the animals with methylprednisolone acetate (20 mg kg−1, i.m.) two days before surgery decreased the rate of skin healing but did not alter the level of albumin peroxidase activity of the plasma. Histology showed that in the animals treated with this drug the re-epithelialization was slower and after 11 days the wound appeared similar in appearance to the 8-day control wounds. In the methylprednisolone-treated animals a positive correlation was observed between the DNA content of regenerating tissue and the hydroxyproline content, whereas a negative correlation was observed in the control wounds. This correlation was in full agreement with the histological observation which showed an increased amount of cytogen collagen in the wounds of the treated animals. The simultaneous study of the biochemical parameters (DNA, proteins, SSAO, hydroxyproline) appears to be a good method for differentiating the pharmacological effects on the different cells which are responsible for wound healing.
γ-Pyrone Compounds as Potential Anti-cancer Drugs
Authors: Liou Shorong-Shii , Shieh Wen-Liang , Cheng Tien-Hsiang , Won Shen-Jeu , Lin Chun-Nan
Published: April 2011

The γ-pyrones, artomunoxanthotrione epoxide, cyclocommunol, cyclomulberrin, and cyclocommunin exhibited potent inhibition of human PLC/PRF/5 and KB cells in-vitro. Dihydroisocycloartomunin showed significant and potent inhibition of human PLC/PRF/5 and KB cells in-vitro, respectively. Cyclomorusin, dihydrocycloartomunin and artomunoxanthone showed significant inhibition of KB cells in-vitro. Based on the above finding and the reported antileukaemic activity of xanthone psorospermin, a series of natural γ-pyrones was prepared and the inhibition of human PLC/PRF/5 and KB cells in-vitro was measured. Structure-activity analysis indicated the epoxide group substituted at 3-hydroxyl and 2,6-; 3,6-; and 3,5-dihydroxyl xanthone enhanced the anti-tumour activity. The epoxide group substituted at the 6-hydroxyl group of 1,6-dihydroxyxanthone did not show anti-tumour activity.
DAU 6215, a novel 5-HT3-receptor antagonist, selectively antagonizes scopolamine-induced deficit in a passive-avoidance task, but not scopolamine-induced hypermotility in rats
Authors: Brambilla Alessandro , Ghiorzi Aldo , Pitsikas Nikolaos , Borsini Franco
Published: April 2011

This study examined the effects of DAU 6215, a selective 5-HT3-receptor antagonist, on either impairment of a passive-avoidance task or hypermotility, both caused by scopolamine in rats. In the first experiment, scopolamine (0·75 mg kg−1, i.p.) disrupted acquisition of a one-trial ‘step through’ passive-avoidance response. Pretreatment with DAU 6215 (1, 10, 30 and 100 μg kg−1, i.p.) antagonized this deficit induced by scopolamine, with a bell-shaped dose-response curve. Scopolamine (0·75 mg kg−1, i.p.) produced a significant increase in locomotor activity which was unaffected by pretreatment with DAU 6215 (10 and 30 μg kg−1, i.p.). The present results further support the suggestion that 5-HT3-receptor antagonists may prevent the memory disturbance caused by a reduction in central cholinergic function in the rat. The inefficacy shown by DAU 6215 on hyperactivity induced by scopolamine appears to rule out the possibility of a pharmacokinetic interference between DAU 6215 and scopolamine.
Solubility, Stability and Ionization Behaviour of Famotidine
Authors: Islam Mohammad S , Narurkar Milind M
Published: April 2011

The pKa of famotidine was determined at 23±0·2°C to be 6·76, 6·98 and 6·89 by a spectrophotometric, solubility, and partitioning method, respectively. The pH-solubility profile of famotidine indicated an intrinsic solubility of 2·7 Mm at 23°C. Degradation of famotidine followed pseudo-first-order kinetics over a pH range of 1–11 at 37±0·2°C and at an ionic strength (μ) of 0·5. The pH-rate profile was accounted for by the specific acid and base catalysed reactions as well as water-catalysed decomposition of both protonated and free famotidine. A pKa of 6·60, determined by potentiometry at 37±0·5°C (μ = 0·5), was used in the kinetic calculations. Maximum stability occurred at pH 6·3. Undissociated acetic acid, dihydrogen phosphate ion and glycine anion were found to contribute to the general acid and base catalyses. pH-dependency of the apparent octanol-water partition coefficient of famotidine indicated a partition coefficient of 0·23 for free famotidine at 23±0·2°C.
Effect of Mode of Incorporation of Disintegrants on the Characteristics of Fluid-bed Wet-granulated Tablets
Authors: Khattab Ibrahim , Menon Anil , Sakr Adel
Published: April 2011

A full factorial experimental design was employed to investigate the effects of mode of disintegrant incorporation and concentration in wet-granulated paracetamol tablets manufactured by topspray fluid-bed. Disintegrants (croscarmellose sodium, sodium starch glycolate, or crospovidone) were incorporated either intragranularly, extragranularly, or distributed equally between the two phases. The results were analysed by a general quadratic equation and response surfaces generated. On examining the results for dissolution studies the combined mode resulted in significantly faster dissolution rates than did the extragranular mode which, in turn, was superior to the intragranular mode of inclusion. These results were reflected in the disintegration studies where the combined mode exhibited the shortest disintegration times for all the disintegrants. Tablet crushing strength was not affected by the mode of incorporation of concentration of the disintegrants. Main as well as interaction effects between the types, mode of incorporation and percent disintegrant employed were significant (P < 0·05) for disintegration time and percent release at 15 min. Croscarmellose sodium exhibited the shortest while crospovidone displayed significantly (P < 0·05) longer disintegration times. Formulations containing crospovidone did not meet official compendial (USP XXII) requirements of 80% in 30 min. In general, croscarmellose sodium and sodium starch glycolate were found to be less sensitive to the mode of incorporation than crospovidone.
Effect of Fat Substitutes, Sucrose Polyester and Tricarballylate Triester, on Digitoxin Absorption in the Rat
Authors: Benmoussa Kamel , Sabouraud Alain , Scherrmann Jean-Michel , Brossard Denis , Bourre Jean-Marie
Published: April 2011

The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on [3H]digitoxin intestinal absorption was studied in the rat using a small intestine in-situ perfusion technique. The effect of SPE and TCTE was compared with that of sunflower oil, oleic acid, and saline. After 120 min perfusion, 5% SPE emulsion significantly reduced (P < 0·001) digitoxin absorption compared with all other treated groups. Five per cent TCTE emulsion had a less marked effect than SPE (P = 0·0002) and did not differ from sunflower oil. No difference was found between saline and 5% oleate emulsion, which did not reduce digitoxin absorption compared with other treated groups (P < 0·02). When taurocholic acid and lipase were added, results for the saline-, TCTE-, and SPE-treated groups were similar to those above, but the sunflower oil-treated group showed significantly enhanced (P < 0·01) digitoxin absorption. Thin-layer chromatography of the lipid phases showed hydrolysis of sunflower oil in the presence of taurocholic acid and lipase, but not of TCTE or SPE. The inhibitory effect of the nonabsorbable fat substitutes on digitoxin absorption could be related to drug sequestration by the persistent oil phase constituted by the undigested and then unabsorbed fat substitutes. That part of digitoxin dissolved in the undigested oil phase is consequently unavailable for intestinal absorption.
Modulatory Role of Magnesium on the Contractile Response of Rat Aorta to Several Agonists in Normal and Calcium-free Medium
Authors: Noguera M Antonia , D’Ocon M Pilar
Published: April 2011

Acute withdrawal of external Mg2+ increased basal tone of rat isolated aorta incubated in the presence of Ca2+. Above normal levels of Mg2+ (1–4 Mm) inhibited basal tone while much higher levels of the divalent cation (64–256 Mm) evoked contractile responses regardless of the presence of Ca2+. Contractile responses to noradrenaline (1μm) and KCl (80 Mm) were inhibited by addition of cumulative concentrations of Mg2+. Acetylcholine-induced contractions in the presence of physiological concentrations of Mg2+ (1 Mm) decreased gradually to the basal tone, but a sustained contraction was observed in the absence of this ion. In Ca2+-free medium, acetylcholine-induced phasic responses indicate the existence of an acetylcholine-sensitive Ca2+ store. KCl induced contraction only in Krebs solution, although a small residual contraction could be observed in Ca2+-free medium in some experiments. Mg2+-depletion in the extracellular medium increased contractile responses induced by acetylcholine and KCl in Ca2+-free medium. These results suggest that extracellular Mg2+ modulates basal tone, Ca2+ channels and responsiveness to various agents in the absence of Ca2+.
Protective effects of cyclodextrin sulphates against gentamicin-induced nephrotoxicity in the rat
Authors: Uekama Kaneto , Shiotani Kazufumi , Irie Tetsumi , Ishimaru Yasuji , Pitha Josef
Published: April 2011

The effects of cyclodextrin sulphates on the development of rat renal dysfunction induced with gentamicin, an aminoglycoside antibiotic, were studied. Daily subcutaneous injection of gentamicin (100 mg kg−1, 14 days) developed nephrotoxicity in the rat as assessed by an increase in serum urea nitrogen and histopathological changes in the renal cortex. When cyclodextrin sulphates were given intraperitoneally at 300 mg kg−1 at 6 h intervals after gentamicin administration, they protected the rat against the drug-induced renal impairment, while the parent cyclodextrins were ineffective. Since post-administration of cyclodextrin sulphates did not reduce the total amount of gentamicin accumulated in the kidney, the protection may occur through interference with intracellular events leading from the drug accumulation to nephrotoxicity. These results suggest that cyclodextrin sulphates are particularly effective in preventing renal failure associated with aminoglycoside treatment.
The effect of surfactant on drug-plastic sorption phenomenon in solution
Authors: Li L C , Zhang H , Pecosky D A
Published: April 2011

The sorption of calcitriol into PVC from an injectable formulation containing Tween 20, a nonionic surfactant, was studied. The amount of drug sorbed by the plastic decreased as the concentration of the surfactant increased. The apparent partition parameter of the drug between PVC strips and the solution was experimentally determined at three different concentrations of the surfactant. A physical model was developed to describe mathematically the partition equilibrium of the drug between the plastic solid phase, the micellar phase of the surfactant, and the aqueous phase of the solution. This model also allowed the calculation of the drug/plastic and drug/micelle partition parameters using the experimentally determined apparent partition parameters.
Gastrointestinal loss of galanthamine hydrobromide in rats in-situ
Authors: Yamboliev I , Mutafova-Yambolieva V , Mihailova D
Published: April 2011

The disappearance kinetics of the acetylcholinesterase inhibitor galanthamine hydrobromide from the gastrointestinal tract of male Wistar rats, 200–250 g, in-situ has been examined. After 30 min the galanthamine loss was 16% in the stomach (pH 2), 54–85% in the duodenum and the successive small intestinal segments (pH 6·8), 43% in the colon and 76% in the rectum. Compared with the other segments, the disappearance rate was higher in the terminal ileum (0·38 × 10−2 mg cm−1 min) and in the rectum (1–27 × 10−2 mg cm−1 min). In the proximal jejunum, terminal ileum and rectum the disappearance rate was linearly dependent on the galanthamine dose (range 0·5–4 mg, 2–16 mg kg−1). The results suggest that when administered orally, rapid galanthamine absorption could be expected all over the gastrointestinal tract due mainly to the passive diffusion mechanism.
The Decomposition of Phenylmercuric Nitrate in Sulphacetamide Drops During Heat Sterilization
Authors: Parkin J E
Published: April 2011

Analytical methods have been developed which enable phenylmercuric nitrate, mercuric ion and diphenylmercury to be measured in sulphacetamide drops. Application of these methods demonstrate that during heat sterilization of both 10 and 30% sulphacetamide drops containing phenylmercuric nitrate, together with disodium edetate and sodium metabisulphite, there is a 20–30% overall loss of phenylmercuric nitrate. This loss occurs mainly due to the phenylmercuric ion establishing an equilibrium with equimolar amounts of mercuric ion and diphenylmercury.
Do antidiarrhoeal opiates accumulate in the rat intestinal lumen?
Authors: De Luca Anthony , Murray Gerard , Coupar Ian M
Published: April 2011

The opiate antidiarrhoeal drugs loperamide (0·6 mg kg−1, i.p.) or difenoxin (0·77 mg kg−1, s.c), were administered in an anaesthetic mixture (pentobarbitone 60 mg kg−1) to rats. A length of jejunum (approx. 30 cm) was cannulated, washed and then perfused with iso-osmotic saline for 20 min. The perfusion commenced 50 min after drug administration and continued for 20 min. The perfusates were collected for analysis of fluid transport rates and antidiarrhoeal drug content. These doses of the antidiarrhoeals caused marked inhibition of intestinal fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide. However, neither of the antidiarrhoeal drugs were detected in the intestinal perfusates (< 0·5 ng by HPLC). The results indicate that loperamide and difenoxin have a different pharmacokinetic profile compared with that previously found for morphine under the same conditions.
The effect of three H2-receptor antagonists on the disposition of midazolam in the rat in-situ perfused liver model
Authors: Hughes C M , Swanton J G , Collier P S
Published: April 2011

The rat in-situ perfused liver model was used to investigate the effect of three H2-receptor antagonists on the pharmacokinetic disposition of the short-acting benzodiazepine, midazolam. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300–350 g). All animals received midazolam 1 mg; the three treated groups received Cimetidine (8 mg), ranitidine (3 mg) or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for midazolam using gas chromatography. The perfusate data indicated that midazolam disposition was impaired at 10, 50 and 60 min of the experimental period following the addition of cimetidine, whereas ranitidine and famotidine produced an effect at 10 min only; midazolam levels in bile were not affected by the presence of an H2-receptor antagonist. It was concluded that the limited inhibitory effect of cimetidine may be attributed to its lack of specificity for CYP3A, the isoenzyme responsible for the metabolism of midazolam.