bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific Binding of Nicergoline on an α1-like Adrenoreceptor in the Rat Retina
Authors: Lograno M D , Tricarico D , Masciopinto V , Scuderi A C 
Published: October 2002

Abstract
Systemic treatment with nicergoline, an ergoline derivative showing α1-antagonist properties, causes vasodilatation in the eye without apparent untoward cardiovascular effects. In the present work we investigated the ability of nicergoline to inhibit the binding of radiolabeled prazosin in the rat retina and cortex.
We found that nicergoline inhibited [3H]prazosin binding in both tissues, being more potent than unlabelled prazosin in the retinal tissue. The competition curves of the ergoline derivative were well fitted by a one-site model in the cortical tissue, with an IC50 (concentration of the drugs needed to inhibit the binding of labelled prazosin by 50%) of 2.54 times 10−8 M, and by a two-site model in the retinal tissue, with IC50 values of 7.08 times 10−12 M and 1.82 times 10−5 M. 2-(2,6 dimetoxyphenoxyethyl) aminomethyl-1,4-benzodioxane hydrochloride (WB4101) and phentolamine, selective ligands for the high-affinity binding site for prazosin, in particular the α1A-site, fully inhibited prazosin binding in the cortex but only partially inhibited prazosin binding in the retina, being less potent in this tissue than either nicergoline or prazosin.
Our results suggest that a binding component of α1-adrenoceptors is expressed to a lesser extent in the retina than the cortex, leading to a reduced response of the retinal tissue to prazosin, and more particularly to WB4101 and phentolamine. The selective binding of the nicergoline on this retinal adrenoreceptor may explain the peculiar efficacy of the drug in ocular pathophysiology.
Comparison of the Vasorelaxing Effect of Cromakalim and the New Inodilator, Levosimendan, in Human Isolated Portal Vein
Authors: Pataricza János , Höhn József , Petri András , Balogh Ádám , Papp Julius Gy 
Published: October 2002

Abstract
In the present study the vasorelaxing capacity of cromakalim, an ATP-sensitive potassium-channel (KATP channel) activator, and that of levosimendan, a new positive inotropic and vasodilating drug with calcium sensitizing and potassium-channel-activating properties, were compared in human isolated portal vein.
Based on the 50% effective concentrations (EC50), levosimendan was found to be about 16-fold more potent (EC50 = 0.281 ± 0.03 μM) as a relaxing agent than cromakalim (EC50 = 4.53 ± 0.12 μM) in noradrenaline-precontracted portal venous preparations. Glibenclamide, the known inhibitor of KATP channels, was able to prevent the cromakalim-induced venodilation completely. Glibenclamide (15 μM) decreased the quasi-maximal effect of levosimendan (at 1.27 μM by about 60%) and also the effects of those submicromolar concentrations of the inodilator (at 0.1 μM by 23%, at 0.3 μM by 27% and at 0.7 μM by 19%, on average) which were therapeutically effective in preliminary human studies.
These findings indicate that, in the human portal vein, both cromakalim and levosimendan are powerful vasorelaxants and that a considerable part of the relaxing effect induced by levosimendan is of cromakalim type.
Protection of Mitochondrial Functions against Oxidative Stresses by Isoflavans from Glycyrrhiza glabra
Authors: Haraguchi Hiroyuki , Yoshida Nobukazu , Ishikawa Harumi , Tamura Yukiyoshi , Mizutani Kenji , Kinoshita Takeshi 
Published: October 2002

Abstract
Isoflavan derivatives, glabridin (1), hispaglabridin A (2), hispaglabridin B (3), 4′-O-methylglabridin (4) and 3′-hydroxy-4′-O-methylglabridin (5), isolated from Glycyrrhiza glabra, were investigated for their ability to protect liver mitochondria against oxidative stresses.
Mitochondrial lipid peroxidation linked to respiratory electron transport and that induced non-enzymatically were inhibited by these isoflavans. Hispaglabridin A (2) strongly inhibited both peroxidations and 3′-hydroxy-4′-O-methylglabridin (5) was the most effective at preventing NADH-dependent peroxidation. 3′-Hydroxy-4′-O-methylglabridin (5) protected mitochondrial respiratory enzyme activities against NADPH-dependent peroxidation injury. Dihydroxyfumarate-induced mitochondrial peroxidation was also prevented by this isoflavan.
Isoflavans from G. glabra were shown to be effective in protecting mitochondrial function against oxidative stresses.
Synthesis and Anti-inflammatory Effect of Chalcones
Authors: Hsieh Hsin-Kaw , Tsao Lo-Ti , Wang Jih-Pyang , Lin Chun-Nan 
Published: October 2002

Abstract
The process of degranulation of mast cells and neutrophils contributes to inflammatory disorders. Activation of microglial cells and macrophages is believed to be involved in inflammatory, infectious and degenerative diseases of the CNS. Combining the potent inhibition of chemical mediators released by the degranulation of mast cells or neutrophils and from the activated microglial cells or macrophages, would lead to a promising antiinflammatory agent for the treatment of peripheral and central inflammation. A series of chalcone derivatives have been reported to have potent anti-inflammatory activity. In an effort to continually develop potent anti-inflammatory agents, novel series of chalcones, 2′-hydroxy- and 2′,5′-dihydroxychalcones were synthesized and their inhibitory effects on the activation of mast cells, neutrophils, microglial cells and macrophages were evaluated in-vitro. The chalcones were prepared by Claisen-Schmidt condensation of appropriate acetophenones with an appropriate aromatic aldehyde. The alkoxychalcones were prepared with appropriate hydroxychalcones and alkyl iodide and the dihydroxychalcones were prepared by hydrogenation of an appropriate chalcone with Pd/C.
Almost all of the hydroxychalcones exhibited potent inhibitory effects on the release of β-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe/cytochalasin B (fMLP/CB). Of the hydroxychalcones, compound 1 was the most potent inhibitor of the release of β-glucuronidase (IC50=1.6 ± 0.2 μM) and lysozyme (IC50=1.4 ± 0.2 μM) from rat neutrophils stimulated with fMLP/CB. Almost all of the 2′,5′-dialkoxychalcones exhibited potent inhibitory effects on nitric oxide (NO) formation from murine microglial cell lines N9 stimulated with lipopolysaccharide (LPS). Of these, compound 11 showed the greatest effect (IC50=0.7 ± 0.06 μM).
The present results demonstrated that most of the chalcone derivatives have an anti-inflammatory effect. The inhibitory effects of dialkoxychalcones, 10–12 on inflammation are probably not due to the inhibition of mast cells and neutrophil degranulation, but are mediated through the suppression of NO formation from N9 cells.
Baicalin Synergy with β-Lactam Antibiotics Against Methicillin-resistant Staphylococcus aureus and Other β-Lactam-resistant Strains of S. aureus
Authors: Liu Iain X , Durham David G , Richards R Michael E 
Published: October 2002

Abstract
Bacterial resistance to antibiotics is a serious global problem and includes strains of β-lactam-resistant Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Novel antimicrobials and/or new approaches to combat the problem are urgently needed. The Chinese herb Xi-nan Huangqin (Scutellaria amoena CM. Wright) has been used in traditional Chinese medicine to treat a wide range of infectious diseases. In this study we have examined the antibacterial action of baicalin, a flavone isolated from the herb.
When combined with 16 μg mL−1 baicalin, minimum inhibitory concentrations (MICs) of benzylpenicillin against MRSA and penicillin-resistant S. aureus were reduced from 125 and 250 μg mL−1 to 4 and 16 μg mL−1, respectively. This activity of baicalin was dose-dependent. Viable counts showed that the killing of MRSA and β-lactam-resistant S. aureus cells by 10 to 50 μgm mL−1 ampicillin, amoxycillin, benzylpenicillin, methicillin and cefotaxime was potentiated by 25 μg mL−1 baicalin.
From the study it was concluded that baicalin has the potential to restore the effectiveness of β-lactam antibiotics against MRSA and other strains of β-lactam-resistant S. aureus. In view of its limited toxicity baicalin offers potential for the development of a valuable adjunct to β-lactam treatments against otherwise resistant strains of microorganisms.
Design, Synthesis and Evaluation of N-Basic Substituted 3-Hydroxypyridin-4-ones: Orally Active Iron Chelators with Lysosomotrophic Potential
Authors: Liu Zu D , Khodr Hicham H , Lu Shu L , Hider Robert C 
Published: October 2002

Abstract
To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentate 3-hydroxypyridin-4-ones with basic chains have been synthesized. As the turnover of ferritin iron is centred in the lysosome, such strategy is predicted to increase chelator efficacy of bidentate ligands.
The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa &gt; 7.0 tended to be more efficient than those with pKa &lt; 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses when compared with N-alkyl hydroxypyridinones.
Optimal effects were observed with the piperidine derivatives 4h and 4i. The derivative 4i at a dose of 150 μmol kg−1 was more effective than 450 μmol kg−1 deferiprone, the widely adopted clinical dose.
In-vitro Metabolism of Retinoic Acid by Different Tissues from Male Rats
Authors: Ahmad Mobasher , Ahmadi Masoud , Nicholls Paul J , Smith H John 
Published: October 2002

Abstract
Significant differences between the metabolism of retinoic acid by different tissues might be an important determinant of the effectiveness of a systemically administered inhibitor at a particular tissue site. Here the metabolism of retinoic acid has been studied in microsomal fractions from different tissues (liver, kidney, intestinal mucosa, lung, skin, brain) of the male rat to determine their relative metabolic activity.
Kinetic analysis revealed major differences between the activity of different tissue microsomes. This is shown by the Vmax values for the metabolism of retinoic acid—liver (102 ± 39.0 pmol (mg protein)−1 min−1) was 100 times more active than the lung (1 ± 0.03 pmol (mg protein)−1 min−1), which was the least active. The range of Km values for microsomes from the different tissues was narrow (0.48–1.40 μM). Taking into account the mass of the tissue, the gross activity ranking for metabolism of retinoic acid was liver&gt;&gt;skin = kidney &gt; brain &gt; intestinal mucosa&gt;&gt;lung.
It is concluded that metabolism of administered retinoic acid occurs mainly in the liver but that cellular retinoic acid levels in some other tissues (skin, kidney, brain) could be reduced (metabolized) to such an extent that higher levels might be observed after the use of inhibitors of retinoic acid metabolism.
A Mechanism of Vasodilatory Action of Polyamines and Acetylpolyamines: Possible Involvement of their Ca2+ Antagonistic Properties
Authors: Myung Chang-Seon , Blankenship James W , Meerdink Denis J 
Published: October 2002

Abstract
Polyamines, a class of low-molecular weight organic polycations, have been shown to produce relaxing effects in vascular smooth muscles, although the mechanism has not been carefully examined. In this study, the mechanism of vascular action of polyamines and their metabolites, acetylpolyamines, was pharmacologically examined in the rabbit isolated thoracic aorta focusing on an endothelium-dependent component of vasodilatation and Ca2+ influx through plasma membrane channels.
Both polyamines and acetylpolyamines (except N1-acetylputrescine, which produced no response or very slight contraction) caused concentration-dependent relaxation in pre-constricted aortic rings containing an intact endothelium. Aortic rings denuded of endothelium were also responsive to both polyamines and acetylpolyamines. Inhibitors of nitric oxide (reduced haemoglobin and Nω-nitro-l-arginine methyl ester), vasodilator prostaglandins (indomethacin) and guanylyl cyclase (methylene blue) did not affect the relaxation induced by both polyamines and acetylpolyamines in either endothelium-intact or -denuded aortic rings. Both polyamines and acetylpolyamines inhibited the concentration-dependent contraction for phenylephrine and K+. The Ca2+ agonist Bay K 8644 induced concentration-dependent contraction in segments of rabbit aorta partially depolarized with 15 mm KCl, and both polyamines and acetylpolyamines relaxed the Bay K 8644-induced contraction in a concentration-dependent manner. Interestingly, both polyamines and acetylpolyamines also decreased contractions evoked by the Ca2+ ionophore A23187. The concentration-response curve to exogenous Ca2+ in K+-depolarization medium (K+ = 120 mm) was shifted to the right by both polyamines and acetylpolyamines. The response elicited by Ca2+ was increased by Bay K 8644 (10−6 m), and this potentiation was also inhibited by both polyamines and acetylpolyamines.
The results indicate that both polyamines and acetylpolyamines can induce vasorelaxation of rabbit thoracic aorta by an endothelium-independent mechanism in-vitro and relax vascular smooth muscle by acting at the plasma membrane level, decreasing the influx of Ca2+. Therefore, polyamines and acetylpolyamines may have Ca2+ antagonistic properties which may, in part, be involved in the mechanism of rabbit aortic vascular smooth muscle relaxation.
The Influence of Crystallization Conditions on the Morphology of Lactose Intended for Use as a Carrier for Dry Powder Aerosols
Authors: Zeng Xian Ming , Martin Gary Peter , Marriott Christopher , Pritchard John 
Published: October 2002

Abstract
Lactose has been widely used as a carrier for inhalation aerosols. The carrier morphology is believed to affect the delivery of the drug. The aim of this study was to investigate the effects of crystallization conditions on the morphology of α-lactose monohydrate intended for use as the carrier for dry powder aerosols.
The crystallization of lactose was carried out from aqueous solutions at different supersaturations, temperatures, different stages of crystallization and in the presence of different water-miscible organic solvents. The majority of lactose crystals were found to be either tomahawk-shaped or pyramidal after crystallization at an initial lactose concentration between 33–43% w/w, but these became prismatic if the lactose concentration was increased to 50% w/w. A further increase in the lactose concentration to 60% w/w led to the preparation of elongated cuboidal crystals. Higher initial lactose concentrations tended to result in the crystallization of more elongated particles. Crystallization at 40°C was shown to prepare lactose crystals with a more regular shape and a smoother surface than those crystallized at 0°C. Lactose particles generated during the later stage of crystallization were found to be more regular in shape with a smoother surface than those prepared in the earlier stage. The addition of 10% (v/v) methanol or ethanol or acetone to the mother liquor increased the growth rate of lactose particles whereas addition of propanol or glycerine inhibited the rate of crystal growth. Lactose crystals prepared in the presence of glycerine were more regularly shaped with a smoother surface than those prepared in the presence of ethanol or acetone. All the resultant crystals were shown to comprise α-lactose monohydrate.
Lactose crystals could be prepared with a precisely defined morphology by means of carefully controlling the crystallization conditions.
Mono- and Biphasic Plasma Concentration-time Curves of Mesalazine from a 500 mg Suppository in Healthy Male Volunteers Controlled by the Time of Defecation before Dosing
Authors: Vree Tom B , Dammers Erik , Exler Peter S , Maes Robert A A 
Published: October 2002

Abstract
This study was based on data from a bioequivalence study (n = 24) of two different formulations of suppositories containing 500 mg mesalazine (formulation I and II), with a similar dissolution profile in phosphate buffer pH 6.8. There was a large intra- and inter-subject variability in the plasma concentration-time curves of mesalazine from both suppositories.
The aim of the investigation was to identify the parameters that caused the observed large variations in release and absorption of mesalazine in the rectum.
Plasma mesalazine and acetylmesalazine, and urine acetylmesalazine concentrations were determined according to validated methods involving HPLC analysis with coulometric detection. Lower limit of quantitation values were respectively 10.4 and 19.4 ng mL−1 in plasma and 0.96 μg mL−1 in urine. The time of defecation before and after insertion was recorded.
There was a clear distinction between subjects who showed monophasic mesalazine release/absorption and those who showed biphasic and more extended release/absorption. With formulation I there was a correlation between time of defecation before dosing and the type of absorption, monophasic and biphasic absorbers showed a significant difference in the time of defecation, e.g. 9.7 ± 5.6 h vs 18.8 ± 11.9 h (P = 0.0218). The impact of time of defecation before dosing was non-significant with formulation II, 16.7 ± 7.2 h vs 15.1 ± 4.2 h (P = 0.67). The impact of the time elapsed between administration and time of defecation after the insertion of the suppository was not significant for the type of release/absorption.
The plasma concentration-time curves of the metabolite ran parallel to that of the parent drug, the more parent drug was released/absorbed, the more was acetylated (P = 0.0013) and excreted into the urine (P = 0.0004). After absorption the compound was metabolized into acetylmesalazine, and renally excreted (12–13% of the dose). Monophasic release/absorption resulted in 7.1% metabolite with I and 10.3% with II (P = 0.0004), while biphasic release/absorption gave 16.8% metabolite with I and 15.5% with II. The renal clearance of the metabolite acetylmesalazine was independent of the observed defecation patterns (300 mL min−1, P &gt; 0.8), stool composition, and type of absorption.
Possible Underestimation of the Channel Conductance Underlying Pinacidil-induced K+ Currents Using Noise Analysis in Pig Urethral Myocytes
Authors: Teramoto Noriyoshi , Brading Alison F , Ito Yushi 
Published: October 2002

Abstract
Electrophysiological and pharmacological properties of the pinacidil-induced K+ currents in isolated cells from pig urethra were investigated using patch-clamp techniques.
Pinacidil (100 μM) induced an outward current at −50 mV which gradually decreased. Under current-clamp conditions, 100 μM pinacidil induced a hyperpolarization that was sustained. This suggests that activation of only a few channels can hyperpolarize the membrane. At a holding potential of −50 mV, glibenclamide inhibited the pinacidil-induced current with a single exponential time course.
Unitary current recordings in symmetrical 140 mM K+ conditions demonstrated that pinacidil activates a 43-pS, glibenclamide-sensitive K+ channel (i.e. KATP channel). Analysis of the basal noise of the pinacidil-induced macroscopic currents from −90 mV to −30 mV yielded estimates of channel conductance (6pS) which were much smaller, and probably an underestimate.
These results indicate that pinacidil induces a glibenclamide-sensitive K+ current through only one type of K+ channel (KATP channel) in pig urethra.
Therapeutic Monitoring of Warfarin: the Appropriate Response Marker
Authors: Costa I M , Soares P J , Afonso M , Ratado P , Lanao J M , Falcão A C 
Published: October 2002

Abstract
Warfarin is a 4-hydroxycoumarin anticoagulant drug used for the prevention and management of thromboembolic and vascular diseases. It acts through the inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of warfarin requires patient monitoring and dosage adjustments, to ensure its safety and efficacy. The aim of this work was to clarify the relationship between traditional (prothrombin time, usually expressed as the international normalized ratio; INR) and alternative (clotting factors II and X) warfarin response markers to establish their usefulness for therapeutic drug monitoring.
Seventy adult outpatients, aged between 31 and 86 years old, were involved in the study. All subjects received warfarin in a monotherapy regimen and had been on a stable dosing schedule for at least two weeks to assure a steady-state condition. A total of 81 prothrombin times (expressed as INR), and factor II and factor X activity were simultaneously determined. Eleven patients presented repeated measurements at different time periods under the same dosing regimen. The results obtained from regression and cluster analysis showed a close relationship between factors II and X (r = 0.73), a weak correlation between INR and both factor II (r = −0.35) and factor X (r = −0.36), and a very slight dependency between warfarin and the response markers used. In addition, it seems that independent of the selected response marker, in long-term warfarin therapy, reproducible responses can be obtained over time if a steady-state condition is achieved. The coefficients of variation for factors II and X were greater (35.44 and 37.93%, respectively) than INR (14.50%), indicating that INR is a more precise measure than either factor II or factor X.
In conclusion, INR appears to be the most appropriate warfarin response marker for therapeutic drug monitoring due to its universality, objectivity as a direct physiological effect measurement, and the available information regarding appropriate endpoints. However, when INR values are not in accordance with patient response therapy, factor II and factor X should be considered as an alternative to optimize warfarin therapy.
Protective Effect of Erdosteine Against Hypochlorous Acid-induced Acute Lung Injury and Lipopolysaccharide-induced Neutrophilic Lung Inflammation in Mice
Authors: Hayashi Ken-Ichi , Hosoe Hisashi , Raise Toshihiko , Ohmori Kenji 
Published: October 2002

Abstract
The effect of erdosteine, a mucoactive drug, on hypochlorous acid (HOCl)-induced lung injury, and the lipopolysaccharide (LPS)-induced increase in tumour necrosis factor-α (TNF-α) production and neutrophil recruitment into the airway, was investigated.
Male BALB/c mice were orally administered erdosteine (3–100 mg kg−1), ambroxol hydrochloride (ambroxol) (3–30 mg kg−1), S-carboxymethyl-L-cysteine (S-CMC) (100–600 mg kg−1) or prednisolone (10 mg kg−1), 1h before intratracheal injection of HOC1 or LPS. In the HOCl-injected mice, erdosteine markedly suppressed increases in the ratios of lung wet weight to bodyweight and lung dry weight to bodyweight, whereas the other mucoactive drugs ambroxol and S-CMC had little effect. Erdosteine also inhibited the LPS-induced neutrophil influx, although it did not affect the increased level of TNF-α in the bronchoalveolar lavage fluid.
The results suggest that attenuation of reactive oxygen species and neutrophil recruitment is involved in the clinical efficacy of erdosteine in the treatment of chronic bronchitis.