bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrostatics of pharmaceutical inhalation aerosols
Authors: Kwok Philip Chi Lip , Chan Hak-Kim 
Published: October 2010

Abstract

Objectives
This review focuses on the key findings and developments in the rapidly expanding research area of pharmaceutical aerosol electrostatics.

Key findings
Data from limited in-vivo and computational studies suggest that charges may potentially affect particle deposition in the airways. Charging occurs naturally in the absence of electric fields through triboelectrification, that is contact or friction for solids and flowing or spraying for liquids. Thus, particles and droplets emitted from pulmonary drug delivery devices (dry powder inhalers, metered dose inhalers with or without spacers, and nebulisers) are inherently charged. Apparatus with various operation principles have been employed in the measurement of pharmaceutical charges. Aerosol charges are dependent on many physicochemical parameters, such as formulation composition, device construction, relative humidity and solid-state properties. In some devices, electrification has been purposefully applied to facilitate powder dispersion and liquid atomisation.

Summary
Currently, there are no regulatory requirements on characterising electrostatic properties of inhalation aerosols. As research in this area progresses, the new knowledge gained may become valuable for the development and regulation of inhalation aerosol products.
Investigations on cellular interaction of polyelectrolyte based nano-walled reservoir using MCF-7 cell lines: a novel chemotherapeutic approach
Authors: Gupta Girish K , Gupta Vivek K , Shukla Prashant , Pant Aditya B , Mishra Prabhat R 
Published: October 2010

Abstract

Objectives
A polyelectrolyte (PE) based nano-walled reservoir (NwR) was developed using alternate deposition of natural polyions on a decomposable core (CaCO3). The system was charged with paclitaxel (PTX) using the trigger property of an organic solvent (NwR-PTX). In addition, the surface of the nano-walled reservoir was modified with PE-PEG2000 (NwR-PTX-PEG)) in order to investigate any changes in the interaction of surface-modified polyelectrolyte shells with breast cancer cells, since surface chemistry greatly influences the performance of microcapsules in the biological environment.

Methods
The surface modification was confirmed by differential scanning calorimetry studies, which showed a shifting of the endothermic peak after pegylation. Layer-by-layer (LBL) growth of the system was confirmed by the sequential change in the ζ-potential. The release of paclitaxel from the formulations followed first order kinetics (r2 = 0.9), indicating matrix diffusion. The interaction of NwR-PTX with MCF-7 cell lines was investigated by coating the system with FITC-dextran (NwR-PTX-FITC) and quantitated using flow cytometry.

Key findings
Cellular uptake of positively charged NwR reached 56% after 4 h and 76% after 24 h. This was reduced significantly after pegylation. The negatively charged NwR reached only 49% after 24 h.

Conclusions
This study opens the possibility of specific targeting of tumour cells that can control the release of chemotherapeutic agent either by means of a physiological or chemical trigger. This suggests potential application of this system as a novel approach for the delivery of chemotherapeutic agents.
Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite,N-desmethylsildenafil, in ratsin vitroandin vivo
Authors: Bae Soo H , Bae Soo K , Lee Myung G 
Published: October 2010

AbstractObjectivesIt has been reported that hepatic cytochrome P450 (CYP)2C9 and CYP3A4 are responsible for the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in humans. However, in-vivo studies in rats have not been reported.MethodsSildenafil (20 mg/kg) was administered intravenously to rats pretreated with sulfaphenazole, cimetidine, quinine hydrochloride or troleandomycin, inhibitors of CYP2C6, CYP2C11, CYP2D subfamily and CYP3A1/2, respectively. In-vitro studies using rat liver microsomes were also performed.Key findingsThe area under the plasma-concentration time curve (AUC) was increased and clearance of sildenafil decreased in rats pretreated with cimetidine or troleandomycin. The AUC ratio for N-desmethylsildenafil (0–4 h): sildenafil (0–∞) was significantly decreased only in rats pretreated with cimetidine. Similar results were obtained in the in-vitro study using rat liver microsomes.ConclusionsSildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N-desmethylsildenafil in humans.
Hypolipidaemic activity of orally administered diphenyl diselenide in Triton WR-1339-induced hyperlipidaemia in mice
Authors: Da Rocha Juliana Trevisan , Sperança Adriane , Nogueira Cristina Wayne , Zeni Gilson 
Published: October 2010

Abstract

Objectives
A significant association between the trace element selenium and hyper-cholesterolaemia has been reported. This study was designed to investigate a potential hypolipidaemic effect of diphenyl diselenide ((PhSe)2) in Triton WR-1339-induced hyperlipidaemia in mice.

Methods
Triton was administered intraperitoneally (400 mg/kg) to overnight-fasted mice to develop acute hyperlipidaemia. (PhSe)2 was administered orally (10 mg/kg) 30 min before Triton. At 24 h after Triton injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances and ascorbic acid levels as well as catalase and glutathione peroxidase activity were recorded.

Key findings
(PhSe)2 administration significantly lowered total cholesterol, non-high-density lipoprotein-cholesterol and triglycerides, whilst it increased high-density lipoprotein-cholesterol levels in plasma of hyperlipidaemic mice. Neither oxidative stress nor the antioxidant effect of (PhSe)2 was observed in the mouse liver in this experimental protocol.

Conclusions
These findings indicated that (PhSe)2 was able to lower plasma lipid concentrations. Further studies are needed to elucidate the exact mechanism by which (PhSe)2 exerted its hypolipidaemic effect in the management of hyperlipidaemia and atherosclerosis.
Poloxamer 407 increases soluble adhesion molecules, ICAM-1, VCAM-1 and E-selectin, in C57BL/6 mice
Authors: Johnston Thomas P 
Published: October 2010

Abstract

Objectives
Soluble shedded forms of cell adhesion molecules (sCAMs) found in plasma are regarded as surrogate markers for the cellular expression of CAMs. The presence of oxidised low-density lipoprotein (ox-LDL) cholesterol and fatty acids in the plasma, hypertriglyceridaemia and reduced plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are all thought to stimulate an increase in the cellular expression of CAMs such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Our objectives were to determine how plasma levels of the soluble CAMs were modulated in a mouse model of dyslipidaemia induced chemically with poloxamer 407, and how these changes might be related to changes in the plasma concentrations of total cholesterol, HDL-C, non-HDL-C and triglycerides.

Methods
C57BL/6 mice were given a single intraperitoneal dose of poloxamer 407 (0.5 g/kg) and plasma concentrations of lipid fractions and sCAMs were measured at predetermined time points thereafter.

Key findings
The plasma concentrations of each sCAM were significantly increased in our mouse model of atherogenic dyslipidaemia compared with control mice administered saline, although the temporal relationship between the plasma sCAM concentration-time profiles and the plasma lipid concentration-time profiles were not coincident.

Conclusions
The atherogenic profile in our mouse model was associated with increases in the plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin. These changes precede the formation of atherosclerotic lesions shown in previous work. This suggests the use of these sCAMs as biomarkers of future atheroma formation in this particular animal model.
Cytotoxicity and antiangiogenic activity of grandisin
Authors: Valadares Marize C , De Carvalho Isabel Crhistyna Teles , Junior Luiz de Oliveira , De Sousa Vieira Marcelo , Benfica Polyana Lopes , De Carvalho Flávio Silva , Andrade Lorenna Vieira Silva , Lima Eliana Martins , Kato Massuo Jorge 
Published: October 2010

Abstract

Objectives
The antitumoural properties of grandisin, a tetrahydrofuran neolignan from Piper solmsianum, were investigated by in-vitro and in-vivo assays using the Ehrlich ascites tumoural (EAT) model.

Methods
Viability of the tumour cells was evaluated by Trypan blue exclusion and MTT methods, after incubation with grandisin (0.017-2.3 μM). The effects of grandisin on the activity of caspase-3, −6, −8, and −9 were also investigated using colorimetric protease kits. In-vivo studies were performed in EAT-bearing mice treated intraperitoneally with 2.5, 5 or 10 mg/kg grandisin for 10 days.

Key findings
Grandisin inhibited the growth of EAT cells, by both methods, with IC50 values less than 0.25 μM. The results showed that the activity of all the caspases studied increased in grandisin-treated cells, when compared with control, non-treated cells. Administering grandisin to EAT-bearing mice increased survival of the animals, in a dose-dependent manner. Simultaneously, we detected a 66.35% reduction of intraperitoneal tumour cell burden in the animals treated with 10 mg/kg grandisin. Additionally, in these animals, the marked increase of vascular endothelial growth factor (VEGF) levels, induced by EAT development, was decreased with treatment with grandisin, resulting in a reduction of 32.1% of VEGF levels in the peritoneal washing supernatant, when compared with the control.

Conclusions
The results demonstrated that grandisin induced in-vitro cytotoxicity and antiangiogenic effects in mice while it acted against tumour evolution, prolonging host survival.
Glucuronidation of piceatannol by human liver microsomes: major role of UGT1A1, UGT1A8 and UGT1A10
Authors: Miksits Michaela , Maier-Salamon Alexandra , Nha Vo Thanh Phuong , Sulyok Michael , Schuhmacher Rainer , Szekeres Thomas , Jäger Walter 
Published: October 2010

Abstract

Objectives
Piceatannol, a dietary polyphenol present in grapes and wine, is known for its promising anticancer and anti-inflammatory activity. The aim of this study was to analyse the concentration-dependent glucuronidation of piceatannol in vitro.

Methods
To determine the glucuronidation of piceatannol, experiments were conducted with human liver microsomes as well as using a panel of 12 recombinant UDP-glucuronosyltransferase isoforms. Furthermore, the chemical structures of novel glucuronides were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Key findings
Along with piceatannol it was possible to identify three metabolites whose structures were identified by LC-MS/MS as piceatannol monoglucuronides (M1–M3). Formation of M1 and M3 exhibited a pattern of substrate inhibition, with apparent Ki and Vmax/Km values of 103 ± 26.6 µm and 3.8 ± 1.3 µl/mg protein per min, respectively, for M1 and 233 ± 61.4 µm and 19.8 ± 9.5 µl/mg protein per min, respectively, for M3. In contrast, formation of metabolite M2 followed classical Michaelis–Menten kinetics, with a Km of 18.9 ± 8.1 µm and a Vmax of 0.21 ± 0.02 nmol/mg protein per min. Incubation in the presence of human recombinant UDP-glucuronosyltransferases (UGTs) demonstrated that M1 was formed nearly equally by UGT1A1 and UGT1A8. M2 was preferentially catalysed by UGT1A10 and to a lesser extent by UGT1A1 and UGT1A8. The formation of M3, however, was mainly catalysed by UGT1A1 and UGT1A8.

Conclusions
Our results elucidate the importance of piceatannol glucuronidation in the human liver, which must be taken into account in humans after dietary intake of piceatannol.
Assessment of the in-vivo drug release from pellets film-coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery
Authors: Freire Cristina , Podczeck Fridrun , Ferreira Dinora , Veiga Francisco , Sousa João , Pena Angelina 
Published: October 2010

AbstractObjectivesThe aim of this study was to test the ability of a colon targeting system comprising pellets film-coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5-aminosalicylic acid; 5-ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control.MethodsSix New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5-ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre-determined times and the plasma analysed by a validated HPLC method with fluorescence detection.ResultsAnalysis of the 5-ASA plasma levels following administration of the uncoated pellets showed a Cmax of 2.38 ± 0.49 μg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (Cmax 0.22 ± 0.19 μg/ml and tmax of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24-h study. They had a drug content of &lt; 40%, suggesting that the film-coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits.ConclusionsResults from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.
Effects of polysorbate 80 on the in-vitro precipitation and oral bioavailability of halofantrine from polyethylene glycol 400 formulations in rats
Authors: Tønsberg Henrik , Holm René , Bisgaard Jette , Jacobsen Jette , Müllertz Anette 
Published: October 2010

Abstract

Objectives
The aim of this study was to examine the effects of formulations of polysorbate 80 (PS 80) and polyethylene glycol 400 (PEG 400) on the precipitation and oral bioavailability of the hydrophobic drug halofantrine.

Methods
The in-vitro dilution profile of the formulations was evaluated in phosphate buffer and in simulated intestinal fluids using a standard dissolution apparatus. The pharmacokinetic profile of the formulations was investigated in fasted rats at two dose levels, 5 and 17.5 mg/kg, with blood sampling by vein puncture in the tail.

Key findings
The solubility of halofantrine was found to be highest in PS 80, and in co-mixtures there was a correlation with the content of PS 80. The in-vitro dilution profile revealed precipitation of halofantrine when dissolved in pure PEG 400, although the precipitation was smaller in the simulated intestinal fluid. Addition of 25% PS 80 to the PEG 400 significantly decreased precipitation. The animals dosed with the PEG 400 formulation had significant lower bioavailability than the PS 80–PEG 400 co-mixtures, possibly due to halofantrine precipitation in the gastrointestinal tract.

Conclusions
Addition of PS80 to the formulation increased the bioavailability of halofantrine and the more compound, the more PS80 was needed to prevent precipitation.
Intracellular pharmacokinetics of telithromycin, a ketolide antibiotic, in alveolar macrophages
Authors: Togami Kohei , Chono Sumio , Seki Toshinobu , Morimoto Kazuhiro 
Published: October 2010

AbstractObjectivesTelithromycin, a ketolide antibiotic, has an antibacterial range that covers intracellular parasitic pathogens that survive or multiply intracellularly in alveolar macrophages. The intracellular pharmacokinetics of TEL in alveolar macrophages was evaluated in vitro.MethodsTelithromycin (50 µm) was applied to NR8383 as cultured alveolar macrophages, followed by incubation at 37°C or 4°C. After incubation, the amount of telithromycin in cells was determined.Key findingsTelithromycin exhibited high accumulation in NR8383 and its intracellular accumulation was temperature dependent. Also, telithromycin distributed to the organelles and cytosol in NR8383 and, in particular, it accumulated in the acidic organelle compartments.ConclusionsThis study suggests that the high accumulation of telithromycin in NR8383 is due to its high influx via active transport systems and trapping in acidic organelles, such as lysosomes. Moreover, this study provides important information for optimizing the treatment of respiratory intracellular parasitic infections based on the intracellular pharmacokinetics of antibiotics and parasitic sites.
CPU228, a derivative of dofetilide, relieves cardiac dysfunction by normalizing FKBP12.6, NADPH oxidase and protein kinase C ε in the myocardium
Authors: Hamed Khan Hussien , Hu Chen , Dai De-Zai , Yu Feng , Dai Yin 
Published: October 2010

Abstract

Objectives
The aim of this study was to determine if CPU228, a derivative of dofetilide, is more effective than dofetilide in attenuating isoproterenol-induced heart failure by recovering downregulated FK506 binding protein (FKBP12.6), and suppressing oxidative stress, upregulated NADPH oxidase and protein kinase C ε (PKCε) hyperphosphorylation in the myocardium.

Methods
Heart failure was induced by isoproterenol (1 mg/kg s.c. for 5 days) in male Sprague-Dawley rats. Intervention with either CPU228 or dofetilide (2 mg/kg on Days 3–5) was then conducted in vivo and in vitro.

Key findings
Isoproterenol produced compromised left ventricular systolic pressure, left ventricular pressure rise (dp/dtmax) and fall (dp/dtmin), and left ventricular end-diastolic pressure, associated with oxidative stress, abnormal FKBP12.6, NADPH oxidase p67phox and PKCε in the myocardium. CPU228 was more effective in attenuating these changes than dofetilide in vivo. Dofetilide produced a prolonged QTc to replace a shortened one. In primary neonatal cardiomyocytes, cultured with isoproterenol and treated with either CPU228 or dofetilide at 10−8, 10−7 and 10−6 mol/l, isoproterenol produced a hyperadrenergic state characterized by downregulated FKBP12.6, upregulated NADPH oxidase p67phox and PKCε in vitro. CPU228 was more effective than dofetilide in recovering these changes in a dose-dependent manner without a prolonged QTc.

Conclusions
CPU228 was more effective than dofetilide in attenuating heart failure by normalizing isoproterenol-induced changes, including downregulation of FKBP12.6, upregulation of NADPH oxidase and PKCε hyperphosphorylation in vivo and in vitro.
The role of erythropoietin in the protection of gastric mucosa from indometacin-induced gastric injury and its relationship with oxidant and antioxidant parameters in rats
Authors: Albayrak Fatih , Odabasoglu Fehmi , Halici Zekai , Polat Beyzagul , Dursun Hakan , Uyanik Abdullah , Bayir Yasin , Koc Feride , Suleyman Halis , Albayrak Yavuz 
Published: October 2010

Abstract

Objectives
Erythropoietin has anti-oxidative and anti-inflammatory activity. We wanted to evaluate its activity in preventing damage to the gastric mucosa.

Methods
We examined the protective effect of erythropoietin on indometacin-induced gastric mucosa damage in the rat stomach and compared its potency with that of famotidine. We also measured effects on oxidant and antioxidant parameters in the rat stomach.

Key findings
Famotidine and erythropoietin 2500 and 5000 IU/kg reduced the ulcer area by 98%, 31% and 58%, respectively, compared with the indometacin group. Superoxide dismutase activity and glutathione level were decreased and myeloperoxidase activity increased in the indometacin group compared with healthy rats. Famotidine and erythropoietin at all doses increased superoxide dismutase and glutathione levels significantly compared with the indometacin group. Myeloperoxidase activity was decreased by erythropoietin and famotidine.

Conclusions
These results support the view that erythropoietin counteracts the effects of indometacin in inducing gastric ulcer and could be used as a an antiulcer compound. Its antiulcer effect is less potent than that of famotidine. The antiulcerogenic effects of erythropoietin may be related to its intrinsic ability to sustain the activities of free-radical scavenging enzymes and the bioavailability of glutathione.
Aloe veragel alleviates cardiotoxicity in streptozocin-induced diabetes in rats
Authors: Jain Neeti , Vijayaraghavan Rajagopalan , Pant Satish Chandra , Lomash Vinay , Ali Mohammed 
Published: October 2010

AbstractObjectivesPersistent hyperglycaemia results in oxidative stress along with the generation of oxygen free radicals and appears to be an important factor in the production of secondary complications in diabetes. The aim of this work was to evaluate markers of oxidative stress in heart tissue along with the protective, antioxidant and antidiabetic activity of 30% Aloe vera gel in diabetic rats.MethodsStreptozocin was given as a single intravenous injection and 30% Aloe vera gel was given in two doses for 20 days, orally. Blood glucose, glycosylated haemoglobin, blood reduced glutathione, serum lactate dehydrogenase and serum creatine kinase levels were measured on day 21 after drug treatment. Heart rate and mean blood pressure were recorded at the end of the study. Different biochemical variables were evaluated in the heart tissue, including thiobarbituric acid reactive substance (TBARS), reduced glutathione, superoxide dismutase and catalase in diabetic and in Aloe vera-treated diabetic rats.Key findingsIn streptozocin diabetic rats, the TBARS level was increased significantly, superoxide dismutase and reduced glutathione significantly decreased, and the catalase level was significantly increased. Aloe vera 30% gel (200 mg/kg) treatment in diabetic rats reduced the increased TBARS and maintained the superoxide dismutase and catalase activity up to the normal level. Aloe vera gel increased reduced glutathione by four times in diabetic rats.ConclusionsAloe vera gel at 200 mg/kg had significant antidiabetic and cardioprotective activity.
Application of hanging drop technique to optimize human IgG formulations
Authors: Li Guohua , Kasha Purna C , Late Sameer , Banga Ajay K 
Published: October 2010

Abstract

Objectives
The purpose of this work is to assess the hanging drop technique in screening excipients to develop optimal formulations for human immunoglobulin G (IgG).

Methods
A microdrop of human IgG and test solution hanging from a cover slide and undergoing vapour diffusion was monitored by a stereomicroscope. Aqueous solutions of IgG in the presence of different pH, salt concentrations and excipients were prepared and characterized.

Key findings
Low concentration of either sodium/potassium phosphate or McIlvaine buffer favoured the solubility of IgG. Addition of sucrose favoured the stability of this antibody while addition of NaCl caused more aggregation. Antimicrobial preservatives were also screened and a complex effect at different buffer conditions was observed. Dynamic light scattering, differential scanning calorimetry and size exclusion chromatography studies were performed to further validate the results.

Conclusions
In conclusion, hanging drop is a very easy and effective approach to screen protein formulations in the early stage of formulation development.