bluuebunny/crossref_metadata_2025_split huggingface dataset:
Release Characteristics of Implantable Cylindrical Polyethylene Matrices
Authors: Ertan G , Karasulu E , Demirtaş D , Arici M , Güneri T 
Published: April 2011

Abstract
The geometrical relationship between a hemisphere and a cylinder has been investigated for controlled-release systems.
The relationship was tested by comparing dissolution results with results from mathematical calculation based on the principles of diffusion for matrix systems. A procedure has been developed for producing implantable, cylindrical, low-density polyethylene matrices, uncoated or coated with a thin impermeable film and a thick paraffin layer except for a hole on the flat faces of the cylinder. Drug matrices were prepared from a blend of sodium salicylate and polymer compressed in an appropriately designed stainless-steel mould at 150°C. Differential scanning calorimetry revealed that no decomposition product was formed in the matrix. When the surface area and the number of holes is increased, drug release also increases. When density is increased, however, drug release decreases significantly. Zero-order drug release was obtained from high-density covered one-hole and two-hole matrices. The diffusion coefficient was calculated as 0.067 day−1.
The study suggested that true zero-order drug release could be obtained by drug diffusion from a hole, rather than from geometric shapes in the matrix systems. In addition, for constant release the diffusion area has to increase by approximately 25 mm2 every day, compared to the area of the previous day, because the diffusion distance increases logarithmically.
Influence of Moderate Haemodilution with Fluosol or Normal Saline on Carbaryl Disposition in Sprague-Dawley Rats
Authors: Shrewsbury R P , Johnson L W , Oliver S R 
Published: April 2011

Abstract
In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations.
The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg−1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL).
These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.
Synthesis of 3-Amino-2-(3-indolyl)propanol and Propanoate Derivatives and Preliminary Cardiovascular Evaluation in Rats
Authors: Pérez-Alvarez Victor , Morales-Ríos Martha S , Hong Enrique , Joseph-Nathan Pedro 
Published: April 2011

Abstract
A series of tryptamine analogues has been prepared and tested for their 5-HT1 receptor agonist properties.
The incorporation of an alkoxy group at the C-5 position of the indole nucleus resulted in a short-lived and dose-dependent immediate antihypertensive and bradycardic response in anaesthetized spontaneously hypertensive rats (SHR). In addition, a carbomethoxy function at the β-position of the side-chain of the tryptamines significantly increased the mean resting arterial blood pressure (MAP) in pithed rats and also produced contraction of the canine basilar artery in a dose-dependent fashion.
Structure-activity relationships (SAR) suggest that the 5-alkoxy group is an important pharmacophore in the production of the antihypertensive effect and that the introduction of a hydroxymethylene group on the side-chain, instead of the carbomethoxy group, changed the receptor affinity profile.
Fluorimetric Determination of Tissue Distribution and Differences Between the Activity of Aspirin Esterases I and II in Mice and Rats
Authors: Benedito Marco A C 
Published: April 2011

Abstract
A modification of available fluorimetric methods, based on the native fluorescence of salicylic acid, has been used to assay the activity of aspirin esterases I and II in small amounts of several tissues from rats and mice.
The results obtained showed that aspirin esterase I from mouse liver and kidney had the lowest activity and that the activity of aspirin esterase II from these organs was greater than that from the same organs from rats. Liver enzyme kinetics and tissue distribution in rats was shown to be similar to previous data obtained using a spectrophotometric method.
This fluorimetric method, which is more sensitive and rapid than the spectrophotometric method, may be useful in studies on aspirin metabolism.
Pharmacokinetics and Kinetic-Dynamic Modelling of Aminophenones as Methaemoglobin Formers
Authors: Marino Mark T , Urquhart Michael R , Sperry Michelle L , von Bredow Jurgen , Brown Larry D , Lin Emil , Brewer Thomas G 
Published: April 2011

Abstract
Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations.
The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid Emax pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a ‘first-pass’ activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h.
Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.
Saturable Urinary Excretion Kinetics of Famotidine in the Dog
Authors: Boom Sandra P A , Hoet Sandra , Russel Frans G M 
Published: April 2011

Abstract
An important elimination route of the histamine H2 antagonist famotidine is active tubular secretion via the renal organic cation transport system. To characterize the excretion kinetics of famotidine in-vivo, the relationship between plasma concentration and urinary excretion rate was investigated in the beagle dog over a wide concentration range. The maximum transport capacity and the apparent Michaelis–Menten constant of tubular secretion were estimated.
Concentration-dependent renal clearance was determined either after intravenous infusion of high doses of famotidine for a short time or during continuous infusion. From individual experiments only indications of saturation were observed; these could not be quantified. A tubular titration curve, in which the active tubular famotidine secretion was plotted against the plasma concentration, was constructed from the data from all the experiments. Active tubular secretion was calculated for each experiment separately by subtracting the famotidine filtration rate from the total excretion rate. A tubular transport maximum of 2400 ± 220 μg min−1 and an apparent Michaelis–Menten constant for tubular secretion of 26 ± 4 μg mL−1 (76 ± 12 μm) were estimated from the curve.
To the best of our knowledge, this is the first time that saturation of famotidine renal clearance has been fully quantified in-vivo. Considering the low therapeutic plasma concentrations of famotidine (&lt; 0.1 μg mL−1), these results suggest that clinically the drug has a low interactive potential.
Kinetics of Bupivacaine After Levcromakalim Treatment in Mice
Authors: Gantenbein M , Attolini L , Bruguerolle B 
Published: April 2011

Abstract
Previous workers have reported that 0.01 mg kg−1 of levcromakalim injected intraperitoneally did not modify bupivacaine-induced neurotoxicity but increased the duration of action of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N-desbutylbupivacaine in mice after a single 0.01 mg kg−1 intraperitoneal injection of levcromakalim.
The kinetic parameters of bupivacaine were determined after a single 20 mg kg−1 intraperitoneal injection of bupivacaine in controls and in levcromakalim-treated mice. It was found that levcromakalim did not change any kinetic parameters of bupivacaine or of its main metabolite, N-desbutylbupivacaine. The previously reported findings of the influence of the low dose (0.01 mg kg−1) of levcromakalim on bupivacaine-induced toxicity agree well with the lack of influence of 0.01 mg kg−1 of levcromakalim on bupivacaine and N-desbutylbupivacaine pharmacokinetics, although the reported increase in the duration of action of bupivacaine after levcromakalim treatment can hardly be explained by the pharmacokinetics of bupivacaine when associated with levcromakalim.
We suggest that levcromakalim might interfere directly with ion-channel block caused by bupivacaine by altering conduction properties or indirectly by enhancing bupivacaine-induced voltage and time-dependent sodium-channel block.
Estimation of the Chemosensitizing Activity of Modulators of Multi-drug Resistance via Combined Simultaneous Analysis of Sigmoidal Dose-Response Curves
Authors: Ecker Gerhard , Schaper Klaus-Jürgen , Chiba Peter 
Published: April 2011

Abstract
The potency of modulators which re-establish sensitivity of resistant tumour cells to cytotoxic drugs is not usually described by ED50 values, even though such values are needed for comparison of modulator activity.
Various methods are reported for the determination of ED50 values of propafenone-type modulators of multi-drug resistance in cytotoxicity assays. Best results were obtained by using a combined simultaneous analysis of dose-response curve families. This approach enables calculation of statistically highly significant ED50 values without any data reduction directly from the original data points obtained in daunomycin cytotoxicity assays.
The method also enables extrapolation of the ED50 values of compounds with low activity or poor solubility, or both.
Antidiabetic Efficacy of BRL 49653, a Potent Orally Active Insulin Sensitizing Agent, Assessed in the C57BL/KsJ db/db Diabetic Mouse by Non-invasive 1H NMR Studies of Urine
Authors: Connor S C , Hughes M G , Moore G , Lister C A , Smith S A 
Published: April 2011

Abstract
High resolution 1H nuclear magnetic resonance (NMR) spectroscopic analysis of biofluids is a recently established tool for evaluating inherited and acquired errors in metabolic control. In the present study 1H NMR analysis of urine was used to monitor efficacy of BRL 49653, a potent and selective antihyperglycaemic agent, following oral administration for up to 36 weeks to the genetically diabetic C57BL/KsJ db/db mouse. The effects of BRL 49653 on carbohydrate and fatty acid metabolism were monitored by determination of changes in concentrations of low molecular weight urinary metabolites.
A qualitative comparison of the NMR spectra of urine from untreated diabetic mice with those of lean littermates and literature examples revealed several abnormalities, the majority of which could be explained in terms of the non-insulin dependent diabetes syndrome exhibited by these animals. Quantitatively the most prominent was the extreme glycosuria of both young (8–12 weeks; 0.9 g glucose kg−1 h−1) and older (42 weeks; 2 g glucose kg−1 h−1) diabetic mice. This was accompanied by the excretion of a number of unassigned sugar derivatives and by ketone bodies. Administration of BRL 49653 (3 μmol kg−1) to db/db mice for 24 days reduced blood glucose concentrations to values comparable with non-diabetic lean littermates and reduced glycosuria by &gt; 90%. BRL 49653 significantly reduced excretion of unassigned sugars, acetate, lactate, and the ketone bodies, acetoacetate, 3-d-hydroxybutyrate and acetone.
The anti-diabetic efficacy of BRL 49653, assessed from the pattern of urinary metabolites, was maintained over a 36-week treatment period. These results demonstrate the value of 1H NMR to evaluate non-invasively the efficacy of novel therapeutic agents.
Physical Stability of Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols
Authors: Dordunoo Stephen K , Ford James L , Rubinstein Michael H 
Published: April 2011

Abstract
The effect of storage on the physical stability of solid dispersions of triamterene or temazepam in polyethylene glycols was studied using differential scanning calorimetry (DSC), particle-size analysis and dissolution methods.
The enthalpies of fusion of the carriers, without included drug and previously fused and crystallized, increased on storage. Analysis of similarly treated solid dispersions, containing either 10% temazepam or 10% triamterene, showed that each drug influenced the morphology of the polyethylene glycol (PEG). The enthalpies and melting points of the solidus components of the dispersions' carriers were initially reduced after preparation, but on storage these increased. The particle sizes of the drugs dispersed in the PEGs increased on storage. The changes in dissolution after storage of triamterene or temazepam dispersions were smaller for dispersions in PEG 1500 than for dispersions in PEGs of higher molecular weight (PEG 2000, PEG 4000 or PEG 6000) in which the reduction in dissolution was particularly marked during the first month of storage. The rank order of changes in dissolution were PEG 1500 ≪ PEG 2000 &lt; PEG 4000 ∼ PEG 6000.
The Mechanism of Excretion of Trientine from the Rat Kidney: Trientine is not Recognized by the H+/Organic Cation Transporter
Authors: Kobayashi Michiya , Tanabe Ryou , Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi 
Published: April 2011

Abstract
Trientine dihydrochloride is used to treat Wilson's disease by chelating copper and increasing its urinary excretion. The mechanism of renal excretion of trientine has been investigated in-vivo and in-vitro.
Trientine clearance in the rat was significantly faster than creatinine clearance. When trientine and the same number of moles of copper ions were administered simultaneously to the rat, however, trientine clearance decreased to almost the same level as the creatinine clearance. To clarify this active excretion system for trientine, the uptake of trientine and a physiological polyamine compound, spermine, was investigated using rat renal brush-border membrane vesicles. Although, because trientine and spermine are organic cations, the H+/organic cation transporter is expected to recognize these compounds, neither an outwardly directed H+ gradient nor an inward Na+ gradient stimulated trientine uptake. [14C]Spermine uptake was, nevertheless, trans-stimulated by both unlabelled spermine and trientine and the trans-stimulating effect of spermine on trientine uptake was, furthermore, completely abolished by addition of copper ions to the incubation medium.
These results suggest that there is a specific transport system for spermine and trientine on the renal brush-border membrane. This transport system contributes to the secretion of trientine in the kidney proximal tubule but does not recognize the trientine-copper complex.
Polyhydroxylated C60, Fullerenol, a Novel Free-radical Trapper, Prevented Hydrogen Peroxide- and Cumene Hydroperoxide-elicited Changes in Rat Hippocampus In-vitro
Authors: Tsai M-C , Chen Y H , Chiang L Y 
Published: April 2011

Abstract
The role of polyhydroxylated C60 (fullerenol), a novel free-radical trapper, in prevention of hydrogen peroxide- and cumene hydroperoxide-elicited damage was studied in hippocampal slices from the rat in-vitro. The interactions of polyhydroxylated C60, adenosine and 6,7-dinitroquinoxaline-2,3-dione (DNQX) were also compared.
Hydrogen peroxide (0.006–0.02%) and cumene hydroperoxide (0.5–1.0 mm) both reversibly reduced the amplitudes of CA1-evoked population spikes in the hippocampal slices. Deferoxamine (1 mm) had little effect on the population spikes. Deferoxamine (1 mm) significantly prevented the hydrogen peroxide (0006%)-elicited inhibition of the population spikes. Polyhydroxylated C60 (01 mm) significantly prevented hydrogen peroxide- or cumene hydroperoxide-elicited reduction of the population spikes and also prevented the effects of hydrogen peroxide and cumene hydroperoxide on paired-pulse facilitation in the hippocampal slice. Adenosine reduced the amplitude of population spikes and promoted paired-pulse facilitation in the CA1 region of the hippocampus. Polyhydroxylated C60 did not alter either of the effects of adenosine on the population spikes. DNQX reduced the amplitude of the population spikes in the CA1 region but did not affect the ratio of paired-pulse facilitation. Fullerenol did not alter either effect of DNQX on the population spikes.
These results suggested that polyhydroxylated C60 prevented hydrogen peroxide- and cumene hydroperoxide-elicited damage in the hippocampus slices. These effects might be associated with the free-radical scavenging activity of polyhydroxylated C60.
Recent Advances in Vaccine Adjuvants for Systemic and Mucosal Administration
Authors: O’Hagan Derek T 
Published: April 2011

Abstract
Although vaccines produced by recombinant DNA technology are safer than traditional vaccines, which are based on attenuated or inactivated bacteria or viruses, they are often poorly immunogenic. Therefore, adjuvants are often required to enhance the immunogenicity of these vaccines. A number of adjuvants which are particulates of defined dimensions (&lt; 5 μm) have been shown to be effective in enhancing the immunogenicity of weak antigens in animal models. Two novel adjuvants which possess significant potential for the development of new vaccines include an oil-in-water microemulsion (MF59) and polymeric microparticles. MF59 has been shown to be a potent and safe adjuvant in human subjects with several vaccines (for example HSV-2, HIV-1 and influenza virus). An MF59 adjuvanted influenza has been recommended for approval in Italy.
Microparticles prepared from the biodegradable polymers the poly(lactide-co-glycolides) (PLG) are currently undergoing extensive pre-clinical evaluation as vaccine adjuvants. Because of their controlled release characteristics, microparticles also possess considerable potential for the development of single dose vaccines. The development of single dose vaccines would offer significant advantages and would improve vaccination uptake rates in at risk populations, particularly in the developing world. In addition to systemic administration, microparticles have also also been shown to enhance the immunogenicity of vaccines when administered by mucosal routes. Therefore microparticles may allow the development of novel vaccines which can be administered by non-parenteral routes. Mucosal administration of vaccines would significantly improve patient compliance by allowing immunization to be achieved without the use of needles.
An alternative approach to the development of mucosally administered vaccines involves the production of genetically detoxified toxins. Heat labile enterotoxin (LT) from Escherichia coli and cholera toxin from Vibrio cholerae are two closely related bacterially produced toxins, which are the most potent adjuvants available. However, these molecules are too toxic to be used in the development of human vaccines. Nevertheless, these toxins have been modified by site-directed mutagenesis to produce molecules which are adjuvant active, but non-toxic. The most advanced of these molecules (LTK63), which has a single amino acid substitution in the enzymatically active subunit of LT, is active as an adjuvant, but non-toxic in pre-clinical models. The approach of genetically detoxifying bacterial toxins to produce novel adjuvants offers significant potential for the future development of mucosally administered vaccines.
Abstract
Authors: Murakami Teruo , Yoshioka Makiko , Yumoto Ryoko , Higashi Yutaka , Shigeki Sadayuki , Ikuta Yoshikazu , Yata Noboru 
Published: April 2011

Abstract
Topical delivery of tranilast (N-(3,4-dimethoxycinnamoyl)anthranic acid), an inhibitor of collagen synthesis and a therapeutic drug for keloid and hypertrophic scar, was examined, in rats, with oleic acid alone or a combination of oleic acid and propylene glycol as penetration enhancer. Evaluation was by measurement of the concentration of tranilast in plasma and in the dialysate from skin microdialysis.
When tranilast at a dose of 1.5 mg was applied topically as an ethanol solution containing 5% polyvinylpyrrolidone on a dorsal skin surface (2.25 cm2), the maximum concentration of tranilast in skin dialysate was approximately 2 μM. When 10 or 20% oleic acid was added to the same ethanol solution the maximum concentration of tranilast in the dialysate increased to 10–20 μM, and this value was further increased to 60 μM by the addition of a combination of oleic acid (10 or 20%) and propylene glycol (10%) to the solution. With the combination of oleic acid and propylene glycol the area under the plot of the concentration of tranilast in skin dialysate against time between 0 and 4 h (AUC0–4) was more than 400-fold that after intravenous administration. The transdermal bioavailability of tranilast as assessed by the AUC0–4 of tranilast in plasma, was 0.2% of the dose applied in the ethanol solution, 3–5% of that applied in the ethanol solution containing oleic acid, and 14–16% of that applied in the ethanol solution containing both oleic acid and propylene glycol.
These results suggest that the topical delivery of tranilast with an absorption enhancer such as a mixture of oleic acid and propylene glycol might be a more effective medication than oral administration of tranilast for the treatment of keloid and hypertrophic scar.