bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic differentiation of drug candidates using system analysis and physiological-based modelling. Comparison of C.E.R.A. and erythropoietin
Authors: Veng-Pedersen Peter , Freise Kevin J , Schmidt Robert L , Widness John A 
Published: October 2010

Abstract
Evaluation of the pharmacokinetics (PKs) in a proper physiological context is paramount to elucidate the factors that may improve a drug's PK properties. Using modern system analysis-based physiological modelling principles, this work applies a novel kinetic analysis framework to a PK comparison of two erythropoietically active drugs, C.E.R.A. (continuous erythropoietin receptor activator) and recombinant human erythropoietin (Epo), aimed at elucidating the main factors responsible for the substantial PK differences seen. The evaluation according to the new model is compared with a compartmental model analysis. Sheep (n = 7 for Epo; n = 8 for C.E.R.A.) received intravenous bolus injections of Epo and C.E.R.A. Baseline and 20–30 blood samples per injection were assayed by radioimmunoassay. Fundamental physiologically based PK building block principles were introduced, proceeding to the construction of a general PK model and several sub-models from which a final PK model was selected based on information theoretical principles. The compartmental comparison analysis use a two-compartment model with central Michaelis-Menten elimination. Several lines of evidence support the hypothesis that the desirable slow elimination of C.E.R.A. relative to Epo is mainly caused by a smaller recirculation extraction fraction, which appears more influential on the elimination kinetics than the mean circulation transit time. The compartmental analysis demonstrates large differences in several PK parameters that contribute to C.E.R.A.'s slower elimination, consistent with the recirculation model analysis. It is hypothesized that C.E.R.A.'s smaller recirculatory extraction fraction is due to a reduced receptor-mediated elimination, consistent with in-vitro measurements where C.E.R.A. shows Epo-receptor binding with a lower association constant and a larger dissociation constant.
Bis(α-furancarboxylato)oxovanadium(IV) prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes
Authors: Zuo Yi-Qing , Liu Wei-Ping , Niu Yan-Fen , Tian Chang-Fu , Xie Ming-Jin , Chen Xi-Zhu , Li Ling 
Published: October 2010

Abstract
Previous studies showed that bis(α-furancarboxylato)oxovanadium(IV) (BFOV), an orally active antidiabetic organic vanadium complex, could improve insulin resistance in animals with type 2 diabetes. The present study has been carried out to evaluate the effects of BFOV on insulin-resistant glucose metabolism using dexamethasone-treated 3T3-L1 adipocytes as an in-vitro model of insulin resistance. The results showed that BFOV, similar to vanadyl sulfate and rosiglitazone, caused a concentration-dependent increase in glucose consumption by insulin-resistant adipocytes. Moreover, BFOV enhanced the action of insulin and completely prevented the development of insulin resistance induced by dexamethasone, leading to glucose consumption equal to that by normal cells. In addition, dexamethasone reduced the mRNA expression of insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4) in 3T3-L1 adipocytes, while BFOV normalized the expression of IRS-1 and GLUT4. These findings suggest that BFOV prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes by enhancing expression of IRS-1 and GLUT4 mRNA.
Astaxanthin, a dietary carotenoid, protects retinal cells against oxidative stress in-vitro and in mice in-vivo
Authors: Nakajima Yoshimi , Inokuchi Yuta , Shimazawa Masamitsu , Otsubo Kazumasa , Ishibashi Takashi , Hara Hideaki 
Published: October 2010

Abstract
We have investigated whether astaxanthin exerted neuroprotective effects in retinal ganglion cells in-vitro and in-vivo. In-vitro, retinal damage was induced by 24-h hydrogen peroxide (H2O2) exposure or serum deprivation, and cell viability was measured using a WST assay. In cultured retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus), astaxanthin inhibited the neurotoxicity induced by H2O2 or serum deprivation, and reduced the intracellular oxidation induced by various reactive oxygen species (ROS). Furthermore, astaxanthin decreased the radical generation induced by serum deprivation in RGC-5. In mice in-vivo, astaxanthin (100 mg kg−1, p.o., four times) reduced the retinal damage (a decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitreal N-methyl-d-aspartate (NMDA) injection. Furthermore, astaxanthin reduced the expressions of 4-hydroxy-2-nonenal (4-HNE)-modified protein (indicator of lipid peroxidation) and 8-hydroxy-deoxyguanosine (8-OHdG; indicator of oxidative DNA damage). These findings indicated that astaxanthin had neuroprotective effects against retinal damage in-vitro and in-vivo, and that its protective effects may have been partly mediated via its antioxidant effects.
Muscarinic, Ca++ antagonist and specific butyrylcholinesterase inhibitory activity of dried ginger extract might explain its use in dementia
Authors: Ghayur Muhammad N , Gilani Anwarul H , Ahmed Touqeer , Khalid Asaad , Nawaz Sarfraz A , Agbedahunsi Joseph M , Choudhary Muhammad I , Houghton Peter J 
Published: October 2010

Abstract
Ginger rhizome (Zingiber officinale) has been used for centuries to treat dementia in South Asia. This study was undertaken to possibly justify its use. A 70% aqueous/methanolic extract of dried ginger (Zo.Cr) was used. Zo.Cr tested positive for the presence of terpenoids, flavonoids, secondary amines, phenols, alkaloids and saponins. When tested on isolated rat stomach fundus, Zo.Cr showed a spasmogenic effect (0.03–5.00 mg mL−1); it relaxed the tissue at concentrations ≥5 mg mL−1. The stimulant effect was resistant to blockade by hexamethonium and methysergide, but sensitive to atropine, indicating activity via muscarinic receptors. In atropinized (0.1 μM) preparations, Zo.Cr (0.3–3.0 mg mL−1) relaxed high K+ (80 mm)-induced contractions, indicating Ca++ antagonism in addition to the muscarinic effect. This possible Ca++ antagonist activity was investigated in Ca++-free conditions, with the inhibitory effect of the extract tested against contractions induced by externally administered Ca++. Zo.Cr (0.1–0.3 mg mL−1), similar to verapamil (0.03–0.10 μm), shifted the contractions induced by externally administered Ca++ to the right, thus suggesting an inhibitory interaction between Zo.Cr and voltage-operated Ca++ channels. Zo.Cr (0.1–3.0 μg mL−1) also potentiated acetylcholine peak responses in stomach fundus, similar to physostigmine, a cholinesterase inhibitor. Zo.Cr, in an in-vitro assay, showed specific inhibition of butyrylcholinesterase (BuChE) rather than acetylcholinesterase enzyme. Different pure compounds of ginger also showed spasmolytic activity in stomach fundus, with 6-gingerol being the most potent. 6-Gingerol also showed a specific anti-BuChE effect. This study shows a unique combination of muscarinic, possible Ca++ antagonist and BuChE inhibitory activities of dried ginger, indicating its benefit in dementia, including Alzheimer's disease.
Reduced prehepatic extraction of nicardipine in the presence of pioglitazone in rats
Authors: Choi Jun-Shik , Koh Young-Youp , Chung Joong-Hwa , Choi Dong-Hyun , Han Hyo-Kyung 
Published: October 2010

AbstractThis study investigated the effect of pioglitazone on the pharmacokinetics of oral and i.v. nicardipine in rats. Pharmacokinetic parameters were determined after nicardipine was administered orally (12 mg kg−1) or i.v. (4 mg kg−1) with or without a single dose of oral pioglitazone (0.3 or 1.0 mg kg−1). Compared with the control group given nicardipine alone, coadministration of pioglitazone significantly decreased the total plasma clearance of orally administered nicardipine (by 40.4–46.3%, P &lt; 0.05) and significantly increased the area under the plasma concentration-time curve (by 81.8–96.3%) and the peak plasma concentration, Cmax (by 56.5–66.8%). Tmax and the terminal plasma half-life of nicardipine were not affected, however. Coadministration of oral pioglitazone did not affect the pharmacokinetics of i.v. nicardipine, implying that pioglitazone may mainly decrease the prehepatic extraction of nicardipine during intestinal absorption. In conclusion, pioglitazone significantly enhanced the oral bioavailability of nicardipine in rats by reducing its presystemic clearance.
Design and synthesis of new symmetrical derivatives of dihydropyridine containing a pyridyl group on the 3, 5-positions and evaluation of their cytotoxic and multidrug resistance reversal activity
Authors: Foroughinia Farzaneh , Javidnia Katayoun , Amirghofran Zahra , Mehdipour Ahmadreza , Miri Ramin 
Published: October 2010

Abstract
Today, chemotherapy is an important part in the treatment of several kinds of cancer; however, the development of drug resistance remains one of the major obstacles in successful chemotherapy. Several types of agents have been recognized as multidrug resistance (MDR) inhibitors, among which the 1,4-dihydropyridines (DHPs) have been investigated the most. P-glycoprotein inhibition has been reported as the main MDR reversal mechanism of DHPs, whilst other mechanisms such as inhibition of topoisomerase II have received less attention. Therefore, in this study new derivatives of DHP have been synthesized. Their cytotoxic activity and their effects in reversing atypical MDR have been evaluated. The results confirmed the appropriate effect of these compounds on atypical MDR. Although it was observed that these compounds had a moderate cytotoxic effect, the cytotoxicity of one compound on the K562 cell line (IC50 = 6.61 μM) was comparable with that of doxorubicin (IC50 = 4.17 μM). Finally, the Ca2+-channel antagonistic activity, an undesired effect for these compounds, was evaluated.
Polysaccharopeptide mimics ciclosporin-mediated Th1/Th2 cytokine balance for suppression of activated human T cell proliferation by MAPKp38 and STAT5 pathways
Authors: Lee Cheuk-Lun , Sit Wai-Hung , Jiang Ping-Ping , So Ivy Wing-Yan , Wan Jennifer Man-Fan 
Published: October 2010

Abstract
The activation of T helper (Th) cell subsets plays an important role in the human immune system. Uncontrolled Th1 and Th2 responses lead to autoimmune and inflammatory diseases, respectively. The identification of agents that modulate the Th1/Th2 cytokines is therefore essential for controlling these diseases. We recently reported that polysaccharopeptide (PSP) from Coriolus versicolor exhibited ciclosporin-like activities to control aberrant T lymphocyte activation. Here, we compared the properties of PSP with ciclosporin on cell proliferation, CD25+ expression, secretion of Th1/Th2 cytokines and activation of mitogen-activated protein kinase (MAPK)p38 and signal transducers and activators of transcription 5 (STAT5) on T cells. The data show that PSP alone suppresses the proliferation of activated T cells. PSP exhibited similar and additive inhibitory effects to ciclosporin to suppress activated T cell proliferation, Th1 cytokines and reduce CD3+/CD25+ cell expression, but not Th2 cytokine expression, which helps the cytokine balance shift towards Th2 dominance. These suppressive actions of PSP involved the MAPKp38 and STAT5 pathways. These findings refine our understanding of the effects of PSP on T lymphocytes and its adjuvant properties with the immunosuppressant ciclosporin for possible control of autoimmune diseases.
β-adrenoreceptor blocking and antihypertensive activity of PP-24, a newly synthesized aryloxypropanolamine derivative
Authors: Nikam Aniket P , Bodhankar Subhash L , Piplani Poonam , Bansal Jyotika , Thakurdesai Prasad A 
Published: October 2010

AbstractPP-24 is a newly synthesized putative β-adrenoceptor antagonist. The objective of the study was to the evaluate β-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg−1) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 μg kg−1) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 μg kg−1). The pA2 of PP-24 to β1-, β2- and β3-adrenoceptors was 7.72 ± 0.082, 7.40 ± 0.082 and 6.39 ± 0.16, respectively. The β1/β2 selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses β-adrenoceptor blockade activity but with non-specific affinity for β1- and β2-adrenoceptor subtypes. The rank order of potency of the antagonists for β1-adrenoceptors was atenolol &gt; PP-24 &gt; propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of β-adrenoceptors.
Therapeutic efficacy of Kangen-karyu against H2O2-induced premature senescence
Authors: Cho Eun Ju , Okamoto Takuya , Yokozawa Takako 
Published: October 2010

Abstract
The anti-aging potential of Kangen-karyu extract was investigated using the mechanisms of the cellular aging model of stress-induced premature senescence (SIPS) in TIG-1 human fibroblasts. SIPS was induced by a sublethal dose of H2O2 and chronic oxidative stress with repeat treatment of low-dose H2O2. Reactive oxygen species generation, lipid peroxidation, and senescence-associated β-galactosidase activity were elevated in TIG-1 cells under SIPS induced by H2O2. However, Kangen-karyu extract led to significant declines in these parameters, suggesting its role in ameliorating oxidative stress-related aging. It was also observed that SIPS due to H2O2 treatment led to the loss of cell viability, whereas Kangen-karyu extract improved cell viability by attenuating H2O2-induced oxidative damage. TIG-1 cells under the condition of SIPS caused by sublethal and chronic low doses of H2O2 showed nuclear factor-κB (NF-κB) translocation to the nucleus from the cytosol, while Kangen-karyu extract inhibited NF-κB nuclear translocation, implying that Kangen-karyu extract could exert an anti-aging effect through NF-κB modulation. In addition, treatment with Kangen-karyu extract under H2O2-induced chronic oxidative stress normalized the cell cycle by reducing the number of cells in the G0/G1 phase and elevating the proportion of those in the S phase, indicating the role of Kangen-karyu extract in cell cycle regulation. On the other hand, Kangen-karyu extract did not exert such an effect on cell cycle regulation under acute oxidative stress induced by sublethal H2O2. Furthermore, treatment with Kangen-karyu extract prolonged the lifespan of TIG-1 cells under SIPS. The present study suggests that Kangen-karyu might play a therapeutic role against the aging process caused by oxidative stress.
Physicochemical interactions between drugs and superdisintegrants
Authors: Fransén Nelly , Morin Malin , Björk Erik , Edsman Katarina 
Published: October 2010

Abstract
We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in-vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in-vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non-ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in-vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in-vivo bioavailability of any of the drug molecules.
Salbutamol relative lung and systemic bioavailability of large and small spacers
Authors: Mazhar Syed H R A , Chrystyn Henry 
Published: October 2010

Abstract
Differences between the size and shape of spacers may affect the emitted dose and provide different effects when interchanged during routine use. Using a urinary pharmacokinetic method we have measured the relative lung and systemic bioavailability from urinary salbutamol excretion 30 min (USAL0.5) and 24 h (USAL24), respectively, after the inhalation of two 100-μg doses from a Ventolin Evohaler when used alone (MDI) and when attached to the Volumatic (VOL) or the Aerochamber Plus (AERO) spacers. The in-vitro properties of the emitted dose were determined. The mean (s.d.) USAL0.5 values following MDI, VOL and AERO (n = 13 volunteers) were 5.7 (1.9), 16.4 (8.2) and 14.8 (7.4) μg, respectively. VOL and AERO were significantly greater (P &lt; 0.001 and &lt; 0.01, respectively) than MDI. Comparison of VOL and AERO was similar with a mean ratio (90% confidence interval) of 108.2 (84.5, 138.6)%. USAL24 values between the three inhalation methods were similar. The values for the mean (s.d.) fine particle dose of two 100-μg doses emitted from MDI, VOL and AERO were 83.0 (6.8), 83.6 (4.6) and 73.6 (2.9) μg and the mass median aerodynamic diameters were 2.7 (0.03), 2.8 (0.07) and 2.9 (0.10) μm, respectively. The results showed that during routine use the Volumatic and the Aerochamber Plus spacers should provide similar lung and systemic delivery when attached to a Ventolin Evohaler.
An investigation into the influence of binary drug solutions upon diffusion and partition processes in model membranes
Authors: Fiala Sarah , Brown Marc B , Jones Stuart A 
Published: October 2010

Abstract
Few studies have assessed the impact of binary systems on the fundamental mathematical models that describe drug permeation. The aim of this work was to determine the influence of varying the proportions of prilocaine and lidocaine in a binary saturated solution on mass transfer across synthetic membranes. Infinite-dose permeation studies were performed using Franz diffusion cells with either regenerated cellulose or silicone membranes, and partition coefficients were determined by drug loss over 24 h. There was a linear relationship between the flux of prilocaine and lidocaine through regenerated cellulose membrane (R2 ≥ 0.985, n = 5) and their normalised ratio in solution. This linear model was also applicable for the permeation of prilocaine through silicone membrane (R2 = 0.991, n = 5), as its partition coefficient was independent of the drug ratio (15.84 ± 1.41). However, the partition coefficient of lidocaine increased from 27.22 ± 1.68 to 47.03 ± 3.32 as the ratio of prilocaine increased and this resulted in a non-linear relationship between permeation and drug ratio. Irrespective of the membrane used, the permeation of one drug from a binary system was hindered by the presence of the second, which could be attributed to a reduction in available membrane diffusion volume.
Effects of intestinal constituents and lipids on intestinal formation and pharmacokinetics of desethylamiodarone formed from amiodarone
Authors: Shayeganpour Anooshirvan , Hamdy Dalia A , Brocks Dion R 
Published: October 2010

AbstractTo model the impact of intestinal components associated with a high fat meal on metabolism of amiodarone, rat everted intestinal sacs were evaluated for their ability to metabolize the drug to its active metabolite (desethylamiodarone) under a variety of conditions. The preparations were obtained from fasted rats or rats pretreated with 1% cholesterol in peanut oil. After isolation of the tissues, the intestinal segments were immersed in oxygenated Krebs Henseleit buffer containing varying concentrations of bile salts, cholesterol, lecithin and lipase with or without soybean oil emulsion as a source of triglycerides. Amiodarone uptake was similar between the five 10-cm segments isolated distally from the stomach. Desethylamiodarone was measurable in all segments. Based on the metabolite-to-drug concentration ratio within the tissues, there was little difference in metabolic efficiency between segments for any of the treatments. Between treatments, however, it appeared that the lowest level of metabolism was noted in rats pretreated with 1% cholesterol in peanut oil. This reduction in metabolic efficiency was not observed in gut sacs from the fasted rats to which soybean oil emulsion was directly added to the incubation media. Despite the apparent reduction in intestinal metabolism, there was no apparent change in the ratio of metabolite-to-drug area under the plasma concentration versus time ratios of fasted rats and those given 1% cholesterol in peanut oil, suggesting that the intestinal presystemic formation of desethylamiodarone is not substantial.
Repeated injection of pegylated liposomal antitumour drugs induces the disappearance of the rapid distribution phase
Authors: Cui JingXia , Li ChunLei , Wang CaiXia , Li YanHui , Zhang Lan , Zhang Li , Yang HaiYan 
Published: October 2010

AbstractUpon repeated administration, empty pegylated liposomes lose their long-circulating characteristics, referred to as the accelerated blood clearance (ABC) phenomenon. To investigate whether cytotoxic drug-containing pegylated liposomes could also elicit a similar phenomenon, two pegylated liposomal antitumour drugs (doxorubicin and mitoxantrone) were prepared, and they were administrated twice in the same animals with a 10-day interval at a dose level of 8 mg kg−1 (pegylated liposomal doxorubicin) and 4 mg kg−1 (pegylated liposomal mitoxantrone). By comparing the overall pharmacokinetics after a single-dose injection with that in animals treated with two doses, it was surprising to find that repeated administration of pegylated liposomal antitumour drugs caused the disappearance of rapid distribution phase instead of the ABC phenomenon, resulting in the conversion of a two-compartment model to a one-compartment model. Further investigation revealed that repeated injection induced the decreased uptake of liposomal antitumour drugs by the spleen at the early time point of 0.5–8 h after injection. In contrast, the deposition of liposomal antitumour drugs into liver was not affected. Therefore, the disappearance of the rapid distribution phase might be related to the reduced spleen uptake at the early time point.