bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin
Authors: Kelder Jan , Funke Carel , de Boer Thus , Delbressine Leon , Leysen Dirk , Nickolson Victor 
Published: April 2011

Abstract
Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated.
Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin.
The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.
Behavioural Subsensitivity Induced by Long-term Administration of a Low Dose of Haloperidol to Rats
Authors: Frussa-Filho Roberto , Abílio Vanessa Costhek , Bergamo Marcelo , Palermo-Neto João 
Published: April 2011

Abstract
This study examines the effects on open-field and stereotyped behaviour of rats of abrupt withdrawal from repeated treatment with a low (0.03 mg kg−1) dose of haloperidol.
Single administration of this low dose of haloperidol significantly increased open-field locomotion without modifying apomorphine (0.5 or 2.0 mg kg−1)-induced stereotyped behaviour. Forty-eight hours after abrupt withdrawal from 0.03 mg kg−1 haloperidol (twice daily for 15 days) a significant decrease in locomotion frequency was observed, but no change was observed in apomorphine-induced stereotypy.
Our results suggest that dopamine autoreceptor supersensitivity might be evaluated in a behavioural situation of absence of postsynaptic dopamine receptor supersensitivity.
Antihypertensive Effect of some Oxazolo[3,2-a]pyridines, Thiazolo[3,2-a]pyridines and Pyrido[2,1-b]oxazines in Conscious Spontaneously Hypertensive Rats
Authors: Moran Asunción , Martín Elena , Velasco Cristina , Martín M Luisa , Roman Luis San , Caballero Esther , Puebla Pilar , Medarde Manuel , Feliciano Arturo San 
Published: April 2011

Abstract
The antihypertensive activity of eighteen oxazolo[3,2-a]pyridine, fhiazolo[3,2-a]pyridine and pyrido[2,1-b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference.
At a dose of 50 mg kg−1 (i.p.) eleven compounds resulted in a significant reduction in mean arterial blood pressure; four of the eleven were particularly effective, resulting in significant hypotension more than 6 h after administration and an effect that was still apparent after 24 h. The hypotension induced by nifedipine gradually decreased, disappearing 6–8 h after administration. The long-lasting activity shown by these compounds is, in general, not accompanied by reflex tachycardia. Intraperitoneal administration of two oxazolo[3,2-a]pyridine derivatives and two pyrido[2,1-b]oxazine derivatives resulted in potent and long-lasting antihypertensive action in SHRs.
Further studies on the mechanism of action of these derivatives might help the determination of better structure–activity correlations and the design, synthesis and evaluation of better antihypertensive agents.
Prediction of the Plasma Concentration Profiles of Orally Administered Drugs in Rats on the Basis of Gastrointestinal Transit Kinetics and Absorbability
Authors: Sawamoto Taiji , Haruta Shunji , Kurosaki Yuji , Higaki Kazutaka , Kimura Toshikiro 
Published: April 2011

Abstract
A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats.
The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems.
We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.
Something in the Air: Endotoxins and Glucans as Environmental Troublemakers
Authors: Young R S , Jones A M , Nicholls P J 
Published: April 2011

Abstract
This review provides a clear explanation of the current status of two common airborne contaminants, lipopolysaccharide and (1.3)-β-D-glucan, in the induction of indoor air-related disease.
A full description of the origin of these two products is given together with information of their structure and function. Details of the biochemical mechanisms by which they interact with human cells and the physiological consequences of these interactions are outlined.
Both compounds play a key role in the induction of airway inflammation and this paper highlights the environmental importance in the work place and home of these inhaled agents in terms of respiratory disease.
Absorption Studies of Albendazole and Some Physicochemical Properties of the Drug and Its Metabolite Albendazole Sulphoxide
Authors: Jung H , Medina L , García L , Fuentes I , Moreno-Esparza R 
Published: April 2011

Abstract
In several studies of patients with neurocysticercosis under treatment with albendazole the pharmacokinetic data were difficult to interpret, probably because of slow and erratic drug dissolution response and absorption problems in-vivo. Because there is no information available about the physicochemical properties of the drug, the aim of this work was to explain this erratic behaviour by fully characterizing the solution behaviour of the drug and its metabolite. To accomplish this, the physicochemical properties, pKa and solubility, and in-vitro plasma binding of albendazole and its main metabolite, albendazole sulphoxide, were studied by conventional methods. The intestinal and gastric absorption and dissolution behaviour of albendazole were also studied.
The solubility of both compounds is very low. Both are amphoteric molecules with two ionization steps, with pKa values of 10.26 and 2.80 for albendazole and 9.79 and 0.20 for albendazole sulphoxide; low pKa values were obtained by performing linear free energy relationship calculations. On the other hand, protein binding studies showed that albendazole is 89–92% bound to plasma proteins whereas for albendazole sulphoxide the figure is 62–67%. This metabolite is bound by albumin and to α1-glycoprotein. Absorption of albendazole occurs along the gastrointestinal tract and is limited by its solubility. Good dissolution profiles were observed when 0.1 M HCl was used as dissolution medium.
The results show that 0.1 M HCl enables discrimination between the drug-release characteristics of different products.
Circadian Variations in the Pharmacokinetics of Pentoxifylline in Man
Authors: Srinivasu P , Rao B Ramesh , Rao Y Madhusudhan , Rambhau D 
Published: April 2011

Abstract
Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and diseased subjects is manifested as circadian rhythms in blood pressure, cardiac output, heart rate, etc. The disposition of several cardiovascular drugs in man has been reported to be time-dependent. This study reports the effect of time of administration on the disposition of pentoxifylline.
Twelve healthy volunteers were treated with 400 mg pentoxifylline orally at 0100, 0700, 1300 and 1900 h in a randomized crossover Latin-square design with a wash-out period of one week. Serum samples were analysed for unchanged pentoxifylline by HPLC. Pharmacokinetic parameters were calculated using a model-independent method. The mean values of various pharmacokinetic parameters after drug treatment at these times were, respectively: maximum plasma concentration (Cmax) 485 ± 174, 646 ± 175, 735 ± 271 and 781±217 ng mL−1; time to reach the maximum plasma concentration (Tmax) 1.90±0.39, 1.66±0.4, 1.31 ± 0.41 and 1.32 ± 0.44 h, mean residence time (MRT) 3.8 ± 0.8, 2.9 ± 0.5, 2.9 ± 0.4 and 2.7 ± 0.3 h, elimination half-life (t1/2) 1.93 ± 0.86, 1.23 ± 0.3, 1.39 ± 0.3 and 1.23 ± 0.18 h and volume of distribution at steady state (Vdss/f) 11991 ± 4862, 8823 ± 3484, 8275 ± 2357 and 7063 ± 1950 mL kg−1. The mean Cmax value was significantly (P &lt; 0.05) lower after drug administration at 0100 h than after other time-points whereas mean Tmax, MRT, Vdss/f and t1/2 values were significantly (P &lt; 0.05) higher.
These variations might be because of time-dependent changes in absorption and biliary excretion of pentoxifylline and should be borne in mind when designing sustained action dosage forms for the drug.
Cytotoxicity of Absorption Enhancers in Caco-2 Cell Monolayers
Authors: Sakai Michinori , Imai Teruko , Ohtake Hiroshi , Otagiri Masaki 
Published: April 2011

Abstract
This study was performed to evaluate the utility of absorption enhancers with reference to mucosal cell cytotoxicity. Overall assessment of the damage to plasma, lysosomal and nuclear membranes by three absorption enhancers, sodium deoxycholate, sodium caprate and dipotassium glycyrrhizinate, was performed on Caco-2 cell monolayers.
The cytotoxicities of sodium deoxycholate (0.02–0.1% w/v), sodium caprate (0.1–0.5% w/v) and dipotassium glycyrrhizinate (0.5–2% w/v) were evaluated by the trypan blue-exclusion test, the protein-release test, the neutral-red assay, the DNA-propidium iodide staining test and the test for recovery of transepithelial electrical resistance (TEER) up to 24 h after treatment with each enhancer. Sodium dodecyl sulphate (SDS; 0.1% w/v), a potent surfactant, was used as positive control. SDS at this level was significantly cytotoxic whereas dipotassium glycyrrhizinate was not cytotoxic in any tests. Results from the trypan blue-exclusion and protein-release tests showed that high concentrations of sodium caprate (0.5% w/v) and sodium deoxycholate (0.1% w/v) were significantly cytotoxic to the plasma membrane. The neutral-red assay, an indicator of damage to lysosomal membranes, revealed that 0.5% (w/v) sodium caprate had no effect whereas the uptake of neutral red was slightly increased by treatment with 0.1% (w/v) sodium deoxycholate, implying that the compound had cell-growth-enhancing activity. Nuclear-membrane damage, as evaluated by the DNA-propidium iodide staining test, was severe in cell monolayers treated with 0.5% (w/v) sodium caprate compared with that induced by 0.1% (w/v) sodium deoxycholate. In the TEER recovery test, TEER failed to recover 24 h after treatment with 0.5% (w/v) sodium caprate and 0.1% (w/v) SDS, but recovered after treatment with 0.1% (w/v) sodium deoxycholate. The recovery of TEER might be related to nuclear membrane damage and cell-growth-enhancing activity.
These results indicate that of the three classes of enhancer, dipotassium glycyrrhizinate was not cytotoxic and that high concentrations of sodium caprate and sodium deoxycholate could damage plasma and nuclear membranes.
Abstract
Authors: Laight D W , Kaw A V , Carrier M J , Änggård E E 
Published: April 2011

Abstract
Nitric oxide (NO)-mediated vasodilation induced by hyperinsulinaemia might involve an indirect action which promotes agonist-stimulated endothelial function. Our aim was to attempt to demonstrate such modulation of endothelium-dependent vasodilation by insulin in the rat isolated aorta.
We found that vasodilation in response to acetylcholine, but not to adenosine diphosphate (ADP), histamine or the calcium ionophore A23187, was modestly enhanced after 20-min pretreatment with human insulin (100 nM) whereas endothelium-independent responses to the NO donor sodium nitroprusside were not significantly affected.
Human insulin thus has the acute pharmacological action of selectively enhancing muscarinic receptor-mediated endothelial function in rat aortic vascular smooth muscle in-vitro.
Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats
Authors: De Campos Rafael O P , Paulino Niraldo , Da Silva Célio H M , Scremin Amarilis , Calixto João B 
Published: April 2011

Abstract
Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil.
The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg−1) or zymosan (40 mg kg−1) were inhibited to different extents by an extract of propolis (1–60 mg kg−1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg−1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg−1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg−1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg−1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg−1 i.p. or 25–100 mg kg−1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg−1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P &lt; 0.01). In contrast with morphine the extract of propolis (. 100 mg kg−1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg−1 i.p.) reversed (P &lt; 0.01) the effect of morphine (5 mg kg−1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg−1 i.p., 30 min previously).
These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.
Effects of Copper-aspirin Complex on Platelet Aggregation and Thrombosis in Rabbits and Mice
Authors: Shen Z Q , Liang Y , Chen Z H , Liu W P , Duan L 
Published: April 2011

Abstract
The effects of intragastric and intraduodenal copper-aspirin complex on rabbit platelet aggregation were observed by Born’s method. Myers’s method was used to evaluate the antithrombotic effect of copper-aspirin complex in mice.
In-vitro copper-aspirin complex selectively inhibited arachidonic acid-induced platelet aggregation with an IC50 value (concentration resulting in 50% inhibition) of 13.2 μM (95% confidence limits 9.1–16.8 μM). Copper-aspirin complex (10 mg kg−1 given intragastrically or intraduodenally) was more potent than aspirin in inhibiting arachidonic acid-induced platelet aggregation. Copper-aspirin complex (10 mg kg−1) had a stronger inhibitory effect and a longer duration of action when given intragastrically than when given intraduodenally. It was shown by radioimmunoassay that copper-aspirin complex significantly reduced the level of thromboxane B2 in plasma while markedly increasing that of 6-ketoprostaglandin F1α (6keto-PGF1α). Copper-aspirin complex (10 mg kg−1 given intragastrically for 7 days) significantly reduced mouse mortality caused by intravenous injection of arachidonic acid.
The results suggest that both in-vitro and in-vivo copper-aspirin complex is more potent in selectively inhibiting arachidonic acid-induced platelet aggregation than aspirin. When given intragastrically the complex has a more potent antiplatelet effect and a longer duration of action than when given intraduodenally. The antithrombotic effect of the complex was more potent than that of aspirin.
Effects of Fluoxetine and Norfluoxetine on 5-Hydroxytryptamine Metabolism in Blood Platelets and Brain after Administration to Rats
Authors: Bourdeaux Roland , Desor Didier , Lehr Paul R , Younos Chafique , Capolaghi Bernard 
Published: April 2011

Abstract
The effects of intraperitoneal administration of fluoxetine (2.5, 5, 10 or 20 mg kg−1) and norfluoxetine (10 mg kg−1) on 5-hydroxytryptamine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) metabolism were examined in the blood platelets and brain of rats killed 3 h after a single dose. Several experiments were performed to evaluate the effect of norfluoxetine.
Plasma 5-HT concentrations decreased significantly (48%) compared with control group results 3h after administration of a single dose of fluoxetine (10 or 20 mg kg−1). Similar plasma 5-HT levels, 0.54 ± 0.04 and 0.56 ± 0.09 mg L−1, respectively, were observed after administration of 10 mg kg−1 fluoxetine or norfluoxetine. In the same way 5-HIAA levels in whole brain were similar, 0.36 ± 0.03 and 0.34 ± 0.01 μg g−1, respectively, after administration of fluoxetine or norfluoxetine. There was a good correlation between plasma and brain levels of fluoxetine (0.962) and norfluoxetine (0.957).
The results suggest that fluoxetine and norfluoxetine lead to reduced levels of 5-HT in platelets and of 5-HIAA in the brain. Like the parent drug, norfluoxetine is a potent and selective inhibitor of 5-HT uptake.
Pharmacokinetic Interaction in Rabbits between a New Anticonvulsant, DL-3-Hydroxy-3-ethyl-3-phenylpropionamide, and Phenytoin
Authors: Medina L , García L , Pérez R , Fernández A , Jung H 
Published: April 2011

Abstract
The effect of phenytoin on the disposition of DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) has been studied in New Zealand white rabbits.
Plasma HEPP levels decreased when the drug was administered with phenytoin. The area under the plasma concentration-time curve was reduced by 56.49% (from 43.23 ± 7.0 to 18.81 ± 2.03 μg h mL−1), the elimination half-life was also significantly (P&lt;0.01) reduced (from 2.68 ± 0.35 to 1.04 ± 0.07 h) and the clearance was increased (from 0.35 to 0.81 L h−1 kg−1). In-vitro protein binding to bovine serum albumin (BSA) and plasma was evaluated by equilibrium dialysis. Plasma protein binding was low (between 33.69 and 37.43% at concentrations ranging from 6.25 to 100 μg mL−1). The compound binds preferentially to albumin with an association constant (Ka) of 3.81 times 103 M−1 at 37°C.
The results suggest a pharmacokinetic interaction between phenytoin and HEPP, probably on the drug-metabolizing enzyme system in the liver.
Can Non-steroidal Anti-inflammatory Drugs Act as Metalloproteinase Modulators? An In-vitro Study-of Inhibition of Collagenase Activity
Authors: Barracchini Annalisa , Franceschini Nicola , Amicosante Gianfranco , Oratore Arduino , Minisola Giovanni , Pantaleoni Giancarlo , Di Giulio Antonio 
Published: April 2011

Abstract
The in-vitro effects of some non-steroidal anti-inflammatory drugs and some analgesic drugs on collagenase activity were studied by use of a self-quenched fluorogenic esapeptide as substrate. The increased fluorescence signal arising as a result of peptide cleavage by collagenase was recorded and related to the inhibitory potency of the drugs. The effective concentrations in collagenase modulation were also correlated with the levels of the drugs in the plasma and synovial fluids of patients receiving therapeutic doses.
Six of the tested drugs, nimesulide, piroxicam, tolmetin, meloxicam, sulindac and sodium meclofenamate, inhibited enzyme activity with IC50 values (concentrations resulting in 50% inhibition) ranging from 1.9 to 28.2 μM and Ki (apparent inhibition constant) ranging from 0.83 to 21.8 μM. Much of the activity was restored after dialysis of the enzyme-drug complex, demonstrating the reversibility of the effect.
Although these results indicate that some anti-inflammatory drugs could modulate enzymatic activity involved in the degradation of the extracellular matrix, their possible pharmacological involvement as collagenase inhibitors in collagen degradative diseases remains to be assessed by clinical studies.