bluuebunny/crossref_metadata_2025 huggingface dataset:
An unusual presentation of patent foramen ovale
Authors: Morjaria Rupal , Tsaloumas Marie , Shah Peter
Published: September 2015

Lesson

We report a case of retinal artery occlusion in a young adult in early pregnancy found to have a patent foramen ovale as the source of the embolism. This report suggests the importance of early cardiac investigation in such individuals.
Differences Between Perceived and Registered Behavior of Basketball Coaches After Shot
Authors: Pérez Benjamin Longarela , Seoane Antonio Montero , García Miguel Saavedra
Published: September 2015

This research examines the behavior of youth club basketball coaches after a shot in real-competition situations. Six licensed coaches of the Spanish Basketball Federation took part in this study; all the teams competed in the Galician league (Spain) in the 2010/2011 and 2011/2012 seasons. There were five men’s teams and one women’s team, with players between 11 and 17 years old. To record the behavior, a new instrument was used based mainly on the Coach Behaviour Assessment System (CBAS), which also incorporates some of the adjustments made in the SOCE ( Sistema Observación Conductas Entrenador developed by Montero). The instrument was designed to analyze the behavior of coaches after their players have taken shots. In total, 38 official matches were analyzed. Registered behaviors were compared with auto-perceived data in the same situation. From the results obtained, significant differences between the registered behavior and the auto-perception of the coaches are evident.
Patellar Tendon–Trochlear Groove Angle Measurement
Authors: Hinckel Betina B. , Gobbi Riccardo G. , Kihara Filho Eduardo N. , Demange Marco K. , Pécora José Ricardo , Camanho Gilberto Luis
Published: September 2015

Background:

The tibial tubercle–trochlear groove (TT-TG) is used as the gold standard for patellofemoral malalignment.

Purpose:

To assess 3 patellar tendon–trochlear groove (PT-TG) angle measurement techniques and the PT-TG distance measurement (tendinous cartilaginous TT-TG) as predictors of patellar instability.

Study Design:

Cohort study (diagnosis); Level of evidence, 3.

Methods:

Three PT-TG angle measurements and the PT-TG distance were measured in 82 participants with patellar instability and 100 controls using magnetic resonance imaging (MRI). Measurement landmarks were the line tangent to the posterior femoral condyles, the deepest point of the trochlea, the transepicondylar line, and the patellar tendon center. All measurements were recorded once by 1 examiner, and the measurements were recorded twice by 2 examiners in a random group of 100 knees. Mean values and standard deviations (SDs) were obtained. Normality cutoff values were defined as 2 and 3 SDs above the mean in the control group. The sensitivity, specificity, and positive likelihood ratio (LR+) were calculated. Inter- and intrarater reliability were assessed based on the intraclass correlation coefficient (ICC).

Results:

The measurements from the patellar instability and control groups, respectively, for angle 1 (16.4° and 8.4°), angle 2 (31° and 15.6°), angle 3 (30.8° and 15.7°), PT-TG distance (14.5 and 8.4 mm), and patellar tilt (21.1° and 7.5°) were significantly different ( P < .05). The angle measurements showed greater sensitivity, specificity, and LR+ than the PT-TG distance. Inter- and intrarater ICC values were >0.95 for all measurements.

Conclusion:

The PT-TG angle and the PT-TG distance are reliable and are different between the patellar instability and control groups. PT-TG angles are more closely associated with patellar instability than PT-TG distance.

Clinical Relevance:

PT-TG angle measurements show high reliability and association with patellar instability and can aid in the assessment of extensor mechanism malalignment. A more sensitive and specific evaluation of extensor mechanism malalignment can improve patient care by preventing both redislocation and abnormal tracking of overlooked malalignment and complications of unnecessary tibial tuberosity medialization.
NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation
Authors: Kim Kyungho , Li Jing , Tseng Alan , Andrews Robert K. , Cho Jaehyung
Published: September 2015

Key Points

NOX2-generated ROS regulate the function of surface receptors required for platelet-neutrophil interactions during vascular inflammation.
BrkAutoDisplay: functional display of multiple exogenous proteins on the surface of Escherichia coli by using BrkA autotransporter
Authors: Sun Fang , Pang Xiaoyun , Xie Tian , Zhai Yujia , Wang Ganggang , Sun Fei
Published: September 2015

Background

Bacterial surface display technique enables the exogenous proteins or polypeptides displayed on the bacterial surface, while maintaining their relatively independent spatial structures and biological activities. The technique makes recombinant bacteria possess the expectant functions, subsequently, directly used for many applications. Many proteins could be used to achieve bacterial surface display, among them, autotransporter, a member of the type V secretion system of gram-negative bacteria, has been extensively studied because of its modular structure and apparent simplicity. However, autotransporter has not been widely used at present due to lack of a convenient genetic vector system. With our recently characterized autotransporter BrkA (Bordetella serum-resistance killing protein A) from Bordetella pertussis, we are aiming to develop a new autotransporter-based surface display system for potential wide application.

Results

Here, we construct a bacterial surface display system named as BrkAutoDisplay, based on the structure of autotransporter BrkA. BrkAutoDisplay is a convenient system to host exogenous genes. In our test, this system is good to efficiently display various proteins on the outer membrane surface of Escherichia coli, including green fluorescent protein (GFP), various enzymes and single chain antibody. Moreover, the displayed GFP possesses green fluorescence, the enzymes CotA, EstPc and PalA exhibit catalytic activity 0.12, 6.88 and 0.32 mU (per 5.2 × 108 living bacteria cells) respectively, and the single chain antibody fragment (scFv) can bind with its antigen strongly. Finally, we showed that C41(DE3) is a good strain of E. coli for the successful functionality of BrkAutoDisplay.

Conclusions

We designed a new bacterial display system called as BrkAutoDisplay and displayed various exogenous proteins on E. coli surface. Our results indicate that BrkAutoDisplay system is worthy of further study for industrial applications.
Strong convergence theorems for equilibrium problems and asymptotically quasi-ϕ-nonexpansive mappings in the intermediate sense
Authors: Ni Ren-Xing , Jin Jian-Shuai , Wen Ching-Feng
Published: September 2015

In this paper, we investigate common solutions to a family of mixed equilibrium problems with a relaxed η-α-monotone mapping and a nonlinear operator equation involving an infinite family of asymptotically quasi-ϕ-nonexpansive mappings in the intermediate sense. Strong convergence theorems of common solutions are established in a strictly convex and uniformly smooth Banach space. These results extend many important recent ones in the literature.
Mechanical ventilation as an indicator of somatic severity of
self-poisoning: implications for psychiatric care and long-term
outcomes
Authors: Baer Elodie , Barré Carole , Fleury Carole , de Montchenu Claire , Garré Jean-Bernard , Lerolle Nicolas , Gohier Bénédicte
Published: September 2015

Background

Somatic severity of a self-poisoning episode varies widely between
patients.

Aims

To determine the correlates (psychiatric profiles, long-term outcome) of
mechanical ventilation used as a proxy to define somatic severity during
a self-poisoning.

Method

All patients who required mechanical ventilation were pair-matched with
ones who did not for age, gender and presence of psychiatric history. One
year after the self-poisoning episode, patients were interviewed using
the Hospital Anxiety and Depression Scale (HADS) and a quality-of-life
assessment questionnaire (Short-Form 12 Health Survey).

Results

The ventilation group (n = 99) more frequently had mood
disorders and less frequently had adjustment disorders
(P = 0.007), with a higher depression score on the
HADS (P = 0.01) than those in the non-ventilation group
(n = 97). Survival curves showed lower survival in
the ventilation group (P = 0.03).

Conclusions

Requirement for mechanical ventilation following self-poisoning is
associated with a high prevalence of mood disorders and poor long-term
outcome.
Dissolution of artemisinin/polymer composite nanoparticles fabricated by evaporative precipitation of nanosuspension
Authors: Kakran Mitali , Sahoo Nanda Gopal , Li Lin , Judeh Zaher
Published: September 2015

Objectives

An evaporative precipitation of nanosuspension (EPN) method was used to fabricate composite particles of a poorly water-soluble antimalarial drug, artemisinin, with a hydrophilic polymer, polyethylene glycol (PEG), with the aim of enhancing the dissolution rate of artemisinin. We investigated the effect of polymer concentration on the physical, morphological and dissolution properties of the EPN-prepared artemisinin/PEG composites.

Methods

The original artemisinin powder, EPN-prepared artemisinin nanoparticles and artemisinin/PEG composites were characterised by scanning electron microscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), dissolution testing and HPLC. The percentage dissolution efficiency, relative dissolution, time to 75% dissolution and mean dissolution time were calculated. The experimental drug dissolution data were fitted to various mathematical models (Weibull, first-order, Korsemeyer–Peppas, Hixson–Crowell cube root and Higuchi models) in order to analyse the release mechanism.

Key findings

The DSC and XRD studies suggest that the crystallinity of the EPN-prepared artemisinin decreased with increasing polymer concentration. The phase-solubility studies revealed an AL-type curve, indicating a linear increase in drug solubility with PEG concentration. The dissolution rate of the EPN-prepared artemisinin and artemisinin/PEG composites increased markedly compared with the original artemisinin powder.

Conclusions

EPN can be used to prepare artemisinin nanoparticles and artemisinin/PEG composite particles that have a significantly enhanced dissolution rate. The mechanism of drug release involved diffusion and erosion.
Preparation and in-vitro/in-vivo evaluation of surface-modified poly (lactide-co-glycolide) fluorescent nanoparticles
Authors: Pamujula Sarala , Hazari Sidhartha , Bolden Gevoni , Graves Richard A , Chinta Dakshina M Devanga , Dash Srikanta , Kishore Vimal , Mandal Tarun K
Published: September 2015

Objective

The aim was to develop biodegradable nanoparticles suitable for cellular delivery of chemotherapeutic drugs.

Methods

Poly (lactide-co-glycolide) (PLGA) nanoparticles were prepared using a modified solvent evaporation method. Chitosan and calcium chloride were tested as surface modifiers. Coumarin-6 was incorporated into some formulations as a fluorescent marker.

Key findings

The median size of the particles was between 400 nm and 7 μm, and scanning electron microscope pictures showed that the particles were smooth and spherical. The zeta potentials of the particles with and without surface modifier ranged between -25.7 mV and -7.0 mV, respectively. Fluorescence microscopy and flow cytometry (FACS) analysis showed that smaller surface-modified particles were efficiently internalised by neoplastic 4T1 cells. Image analysis of frozen tissue sections from Balb/c mice given nanoparticles via the tail vein showed that the particles were distributed preferentially into the lungs, followed by the liver, spleen, kidney and heart.

Conclusions

Chitosan-modified PLGA nanoparticles showed significant uptake by neoplastic 4T1 cells, and were distributed to several major organs frequently seen as sites of cancer metastasis in mice.
Therapeutic 188Re-lanreotide: determination of radiopharmacokinetic parameters in rats
Authors: Molina-Trinidad Eva M , De Murphy Consuelo Arteaga , Jung-Cook Helgi , Stack Eduardo Murphy , Pedraza-Lopez Martha , Morales-Marquez José Luis , Serrano Guadalupe Vertiz
Published: September 2015

Objectives

The radiopharmacokinetic parameters of the therapeutic radiopharmaceutical 188Re-lanreotide were compared in rats implanted with hepatocarcinoma tumours (n= 18) and healthy rats (n= 18).

Methods

Rats were injected with approximately 1.8 MBq 188Re-lanreotide (0.1 ml) via the tail vein and blood samples were obtained. The activity per gram of tissue (%IA/g) was calculated and the radiopharmacokinetic parameters determined. Data were fitted using a two-compartment model.

Key findings

Significant differences were found between healthy and hepatoma rats for beta elimination half-life (22.56 vs 48.14 h); transference constants K10 (ke) (6.44 vs 3.05 h-1) and K12 (2.76 vs 7.09 h-1); volume of distribution (2.06 vs 5.45 ml); mean residence time (66.58 vs 95.50 h) and apparent volume of distribution at steady state (131.30 vs 810.37 ml). The tumour/organ ratios after 24 h were 11.20 for tumour/muscle, 8.00 for tumour/liver and 7.72 for tumour/bone. The scintigraphic images obtained therefore had high resolution.

Conclusions

188Re-lanreotide had a prolonged beta elimination half-life and increased volume of distribution in rats with hepatocellular carcinoma. This may be beneficial in the diagnosis and therapy of metastatic lesions in patients with cancer.
Systemic RANK-Fc protein therapy is efficacious against primary osteosarcoma growth in a murine model via activity against osteoclasts
Authors: Akiyama Toru , Dass Crispin R , Shinoda Yusuke , Kawano Hirotaka , Tanaka Sakae , Choong Peter F M
Published: September 2015

Objectives

Osteosarcoma (OS) is the most common primary malignant bone tumour, and mainly affects adolescents and young adults. Although there has been substantial improvement in management of OS with surgery and chemotherapy, further survival increase has not been achieved over the past two decades.

Methods

We focused on the receptor activator of nuclear factor κB ligand (RANKL)–osteoclast (OCL) system as a biological target for OS. RANKL is a critical factor for OCL formation and bone resorption activity. The primary lesion in bone and ensuing metastasis in OS both require the induction of OCLs. RANK-Fc is a potent RANKL antagonist and inhibitor of OCL formation and activity.

Key findings

In an orthotopic model in Balb/c nu/nu mice, a twice weekly dosing regimen of 350 μg of RANK-Fc per mouse subcutaneously (n= 5) reduced lung metastasis (P > 0.05), preserved bone structure and reduced tartrate-resistant acid phosphatase (TRAP)+ OCLs (P < 0.005) in OS-bearing bone. In vitro, RANK-Fc suppressed OCL formation (P < 0.005), bone resorption activity (P < 0.005) and RANKL-induced anti-apoptosis (P < 0.5) of OCLs.
Effect of repeatedly given CDP-choline on cardiovascular and tissue injury in spinal shock conditions: investigation of the acute phase
Authors: Coskun Cenk , Avci Berrin , Ocak Nihal , Yalcin Murat , Dirican Melahat , Savci Vahide
Published: September 2015

Objectives

The protective effect of CDP-choline in spinal cord transection and the mediation of its cardiovascular effects were investigated.

Methods

Spinal cords of rats were transected at the T1–T2 levels. CDP-choline (250 mg/kg; intravenous) was administered 2 h and/or 24 h after the injury.

Key findings

Spinal cord transection caused severe tissue damage, decreased mean arterial pressure, heart rate, plasma adrenaline, and noradrenaline but increased plasma vasopressin levels. Repeated CDP-choline treatment attenuated the degree of tissue injury. Administration of CDP-choline at 2 h after transection transiently increased blood pressure and decreased heart rate, while it produced a small decrease in blood pressure and heart rate when it was given at 24 h. Plasma adrenaline levels were higher in the group where CDP-choline was given repeatedly. Plasma noradrenaline and vasopressin levels did not change additionally after CDP-choline injections in all groups. In order to determine if CDP-choline attenuates the oxidative injury induced by transection, we measured blood superoxide dismutase, glutathione peroxidase activity and malondialdehyde levels. Repeated CDP-choline administration decreased blood superoxide dismutase and glutathione peroxidase activity without any effect on malondialdehyde levels.

Conclusions

Data indicate that repeated intravenous CDP-choline treatment prevents tissue damage in spinal shock conditions in the acute phase. The cardiovascular effects of the drug do not seem to be responsible for this protection but the drug-induced attenuation of the oxidative stress may play a role.
Modulation of oxidative/nitrosative stress and mitochondrial protective effect of Semecarpus anacardium in diabetic rats
Authors: Jaya Aseervatham , Shanthi Palanivelu , Sachdanandam Panchanadham
Published: September 2015

Objectives

Oxidative and nitrosative stress play an important role in the complications of diabetes mellitus. Free radicals are produced when there is an electron leak in the mito-chondria and a change in the mitochondrial membrane potential. The present study was undertaken to investigate the role of Semecarpus anacardium in protecting the mito-chondria by modulating the production of reactive oxygen species and reactive nitrogen species in diabetic rats.

Methods

Diabetes was induced using streptozotocin at a dose of 50 mg/kg body weight and, starting 3 days after the induction, Semecarpus anacardium nut milk extract was administered for 21 days. The same duration of study was used for control, diabetes-induced and drug control groups, together with a group treated with metformin. After the experimental period, the animals were sacrificed and the levels of superoxide, hydrogen peroxide, nitrate and nitrite were estimated. Changes in mitochondrial membrane potential, intracellular reactive oxygen species and intracellular calcium were also determined. Confocal laser microscopic images were taken for mitochondria isolated from the liver and kidneys.

Key findings

The results of the study revealed that Semecarpus anacardium was able to decrease the production of reactive oxygen and nitrogen species, and reverse the changes in mitochondrial membrane potential and the influx of calcium into the mitochondria.

Conclusions

The mitochondrial protective effect may be mediated by scavenging of free radicals and complexing of metal ions by virtue of the antioxidative effect of Semecarpus anacardium.
Structural requirement of spirostanol glycosides for rat uterine contractility and mode of their synergism
Authors: Yu Zu-Yin , Guo Lin , Wang Bo , Kang Li-Ping , Zhao Zhen-Hu , Shan Ya-Jun , Xiao He , Chen Jia-Pei , Ma Bai-Ping , Cong Yu-Wen
Published: September 2015

Objectives

Total steroidal saponins extracted from the rhizome of Paris polyphylla (TSSP) have been used in China for the treatment of abnormal uterine bleeding. The aim of this study was to analyse the structure–activity relationship of steroidal saponins purified from P. polyphylla Sm. var. yunnanensis on rat myometrial contractions, and investigate the synergism among themselves as well as with known inherent agonists, such as Prostaglandin F2α (PGF-2α).

Methods

In this study, 22 steroidal saponins purified from TSSP were screened for their contractile activity in isolated uterine strips from estrogen-primed rats.

Key findings

It was shown that spirostanol glycosides exhibited inducible or inhibitory activity in rat uterine contraction based on the difference of their structures, which was not only attributed in part to the number, the length and the position of sugar side chains attached by a glycoside, but also related to the structure of the aglycone. Furthermore, synergistic actions were observed among pennogenin or diosgenin glycosides as well as with the known inherent agonist PGF-2α, indicating they may share, at least in part, similar pathways with PGF-2α in stimulating myometrial contractions. Finally, the contractile response of rat myometrium to spirostanol glycosides was significantly enhanced with advancing pregnancy.

Conclusions

Together, these data support the possibility that some spirostanol glycosides may represent a new type of contractile agonist for the uterus and their synergism may be responsible for the therapeutic effect of TSSP on abnormal uterine bleeding.
From sentencing to execution – the processes of apoptosis
Authors: Moffitt Kelly L , Martin S Lorraine , Walker Brian
Published: September 2015

Objectives

Cell proliferation and apoptosis play a major role in maintaining homeostasis and as such any disruption within these processes can lead to disease states. Apoptosis occurs in three non-distinct phases – induction, effector and degradation – and can be executed through both the extrinsic and intrinsic pathways in addition to recognised sub-pathways such as the p53 and lysosomal pathways. This review article highlights these pathways, incorporating an overview of the molecular regulators of apoptosis.

Key findings

These regulators include the prominent apoptotic players ‘the caspases’ in addition to the main regulators of the Bcl-2 family. Increased understanding of the physiological processes of apoptosis at the molecular level not only offers an insight in disease pathogenesis but, in addition, allows for the development of diagnostic, prognostic and therapeutic tools.

While apoptosis remains the key player in cellular death, other processes cannot be dismissed. Many other proteins, in addition to caspases, within apoptotic pathways have been identified. Research continues into establishing the precise aspects of their molecular mechanisms of action and inter-relationships. Inappropriate apoptosis due to dysregulation of cell death pathways provides a plethora of molecular checkpoints that can be targeted and modulated as part of therapeutic intervention. Increased research into these areas will prove useful for the design of novel chemotherapeutic drugs, an area that is particularly important due to increased risk of chemoresistance.
Proteases implicated in apoptosis: old and new
Authors: Moffitt Kelly L , Martin S Lorraine , Walker Brian
Published: September 2015

Objectives

The role of proteases in the regulation of apoptosis is becoming increasingly apparent. Whilst many of these proteases are already characterised, some have yet to be identified. Traditionally caspases held the traditional role as the prime mediators of apoptosis; however, attention is now turning towards the contribution made by serine proteases.

Key findings

As unregulated apoptosis is implicated in various disease states, the emergence of this proteolytic family as apoptotic regulators offers novel and alterative opportunities for therapeutic targets.

This review presents a brief introduction and overview of proteases in general with particular attention given to those involved in apoptotic processing.
Effect of acute hepatic failure on the hepatic first-pass effect of 5-fluorouracil in rats
Authors: Nagata Masashi , Hidaka Yumi , Hidaka Muneaki , Kawano Yohei , Iwakiri Tomomi , Okumura Manabu , Arimori Kazuhiko
Published: September 2015

Objectives

In cancer chemotherapy for hepatocellular carcinoma, 5-fluorouracil is widely used and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and reduce systemic toxicity. 5-Fluorouracil is eliminated primarily by the liver and so the hepatic first-pass effect after intrahepatic arterial administration of 5-fluorouracil may be lower in patients with hepatic failure, and systemic toxicity may not be reduced. In this study, we have investigated the effect of acute hepatic failure on the first-pass effect of 5-fluorouracil in rats.

Methods

Experimental acute hepatic failure was induced by treatment with carbon tetrachloride (CCl4). 5-Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of rats at a dose of 1.25 mg/kg.

Key findings

Hepatic availability in 50% CCl4-treated (severe hepatic failure) rats was higher than in controls.

Conclusions

The hepatic first-pass effect after intrahepatic arterial administration of 5-fluorouracil was lower in severe hepatic failure. Therefore, the reducing effect of the systemic toxicity after intrahepatic arterial administration may be lower in severe hepatic failure.
Influence of etoricoxib on anticonvulsant activity of phenytoin and diazepam in experimental seizure models in mice
Authors: Jayaraman R , Manisenthil K T , Anitha T , Joshi Vishal D , Palei Narahari N , Gajera Kalpesh , Ladani Krupali
Published: September 2015

Objectives

Our aim was to investigate the effect of etoricoxib on the anticonvulsant activity of phenytoin and diazepam against seizure models in mice. In addition the acute adverse effect of etoricoxib was assessed with a chimney test.

Methods

The maximal seizure pattern was induced in mice by giving an alternating current of 50 mA for 0.2 s, while chemical seizures were induced by intraperitoneal injection of pentylenetetrazole at its CD97 dose (97% convulsive dose for the clonic phase). Test drug was administered 45 min before the electrical or chemical induction of seizures in combination with conventional antiepileptics. The ability of the test drug to reduce or abolish the extensor phase of maximal electroshock and clonic-type seizures in the chemical induction method was selected as anti-seizure criteria.

Key findings

Concurrent treatment with etoricoxib at an oral dose of 10 mg/kg reduced the anticonvulsant potency of phenytoin. The protective effects of diazepam against pentylenetetrazole-induced convulsions was significantly increased and the mortality rate was reduced by concurrent treatment with etoricoxib (10 mg/kg p.o.) when compared with diazepam groups. No neurotoxic effect was observed with etoricoxib (10 mg/kg p.o.) and it had no impact on motor coordination in the chimney test in mice. Etoricoxib applied at its highest dose (10 mg/kg) significantly enhanced the free plasma levels of diazepam whereas the free plasma levels of phenytoin were significantly reduced.

Conclusions

The obtained results suggest that the preferential cyclooxygenase-2 inhibitor etoricoxib significantly reduced the anticonvulsant action of phenytoin and significantly increased the beneficial action of diazepam against maximal electroshock and pentylenetetrazole-induced convulsions in a mouse model.
Uptake of nicotine from suspension culture of Nicotiana tabacum by molecularly imprinted polymers
Authors: Abdelkader Mohamed Salaheldin A , Lockwood Brian , Sansongsak Proramate
Published: September 2015

Objectives

The aim was to use molecularly imprinted polymers (MIPs) for the selective recovery of nicotine in plant cell cultures. MIPs can selectively uptake nicotine from suspension cultures of N. tabacum, and therefore may be useful for improving levels of secondary metabolites in plant cell cultures.

Methods

Suspension cultures of N. tabacum were initiated from callus and maintained in liquid Murashige and Skoog (MS) media containing 3% w/v sucrose, 0.1 mg/l α-naphthaleneacetic acid acid (NAA) and 0.25 mg/l kinetin. Tween 80 at 1% was used for permeabilisation of cell cultures. Pre-weighed XAD-2 and two types of synthesized polymers, MIPs (A and B with one and two functional monomers, respectively) and corresponding non-imprinted polymers (NIPs), A and B, were introduced aseptically into the permeabilised suspension cultures of N. tabacum, the nicotine contents of polymers were determined by gas chromatography and the adsorption yield of polymers were determined.

Key findings

Cell cultures of N. tabacum accumulated nicotine alkaloid intracellularly in varying levels, 6.8–14.9 mg/l fresh weight. MIPs were able to uptake 50–70% of released nicotine in suspension cultures of N. tabacum, whereas XAD-2 recovered only 30–40%. The total levels of accumulated nicotine were enhanced up to 20 mg/l by simultaneous use of Tween 80 and MIPs.

Conclusions

The findings indicate the potential use of MIPs to uptake nicotine from suspension cultures of N. tabacum, and increase productivity of secondary metabolites in plant cell cultures.
Change in tolbutamide permeability in rat jejunum and Caco-2 cells by Sho-saiko-to (Xiao Chai Hu Tang), a Chinese traditional medicine
Authors: Nishimura Nobuhiro , Uemura Tomichika , Iwamoto Kikuo , Naora Kohji
Published: September 2015

Objectives

This study was designed to investigate the effects of Sho-saiko-to (Xiao Chai Hu Tang), a Chinese traditional medicine, on the membrane permeability of tolbutamide in the intestinal tract. We carried out an in-situ loop study with rat jejunum and a transport study with Caco-2 cell monolayers.

Methods

In the in-situ loop study, absorption clearance of tolbutamide was estimated from the drug concentrations in the loop and plasma. The apical-to-basolateral and basolateral-to-apical transport of tolbutamide and d-mannitol, a paracellular transport marker, was assessed using Caco-2 cell monolayers cultured on a polycarbonate membrane.

Key findings

The absorption clearance of tolbutamide was enhanced by a concomitant dose of Sho-saiko-to over 10 min in the rat in-situ loop. Sho-saiko-to increased the apical-to-basolateral transport of tolbutamide, whereas the basolateral-to-apical transport of this drug was reduced by Sho-saiko-to. On the other hand, in both directions the Papp of d-mannitol was reduced by the presence of Sho-saiko-to. Furthermore, the apical-to-basolateral transport of tolbutamide in ATP-depleted Caco-2 cells was diminished by Sho-saiko-to. These findings suggest that Sho-saiko-to can facilitate the epithelial membrane permeability of tolbutamide across the rat jejunum in-situ and Caco-2 cell monolayers. Since Sho-saiko-to suppressed the passive transport of tolbutamide from the apical-to-basolateral side, enhanced permeability may be related to effects of Sho-saiko-to on the energy-dependent transport of tolbutamide in the intestine.

Conclusions

Our findings suggest that Sho-saiko-to might facilitate the energy-dependent transport of tolbutamide across the rat jejunum in-situ and Caco-2 cell monolayers.
Recent advances in skin ‘barrier’ research
Authors: Rawlings Anthony V
Published: September 2015

Objectives

Our knowledge on the complexity of stratum corneum biology, chemistry and biophysics has grown over the last decade. This and the intricate control mechanisms in the stratum corneum that bring about its full and proper structural maturity will be reviewed.

Key findings

The importance of the total architecture of the stratum corneum in relation to desquamation and barrier function, the role of the corneodesmosomes and their degrading enzymes, new insights into the importance of natural moisturising factor and the emerging knowledge on the chemical antimicrobial barrier of the stratum corneum are discussed.

Despite our increasing knowledge of the complexity of stratum corneum, we are still far from understanding its intricate control mechanisms that bring about its maturity and desquamation.
Dynamic foams in topical drug delivery
Authors: Zhao Yanjun , Jones Stuart A , Brown Marc B
Published: September 2015

Objectives

Pharmaceutical foams are not new inventions and their application in topical therapy can be traced back three decades. However, foam formulations have been gaining in popularity with over 100 patents published globally in the last 10 years alone. The aim of this paper is to review the current status and explore the future potential of dynamic foam vehicles in the field of topical drug delivery.

Key findings

The use of foam technology to deliver a range of topical active agents has been claimed, including sun-screening compounds, corticosteroids, and antibacterial, antifungal and antiviral agents. Although foams present distinct application advantages and improved patient compliance, the real reason for the rapid growth of topical foam technology is that foams as elegant, aesthetic and cosmetically appealing vehicles provide an alternative, promising formulation strategy in the highly competitive dermatological market. Although there is a plethora of published data proving the safety profiles of topical foams there is a lack of sufficient clinical evidence to demonstrate any superiority of foams over other traditional topical vehicles such as creams and ointments for drug delivery.

Recent literature suggests that when foams are properly engineered using the advances of in situ analysis techniques, the enhancement of topical drug delivery via engineering this type of vehicle can be achieved.
Enhanced skin permeation and hydration by magnetic field array: preliminary in-vitro and in-vivo assessment
Authors: Benson Heather A E , Krishnan Gayathri , Edwards Jeffrey , Liew Yih Miin , Wallace Vincent P
Published: September 2015

Objectives

The aim of the study was determine the effect of magnetic film array technology on the skin permeation of urea.

Methods

A 5% urea gel was applied to human epidermal membrane in vitro and human skin in vivo. Application of gel with magnetic film array and plastic occlusive film was compared with application of gel with a plastic occlusive film and non-magnetic film. In-vitro epidermal penetration was determined using a Franz-type diffusion system. In-vivo permeation and changes in epidermal properties were visualised by optical coherence tomography.

Key findings

The mean cumulative permeation of urea over 2 h for magnetic film array application was 89.54 ± 7.34 μg/cm2 as compared with 20.83 ± 2.02 μg/cm2 for passive occluded application (mean ± SEM, n = 9/8), representing greater than 4-fold increase over the 2-h application time period. Administration of urea with the magnetic film array resulted in the lag time being reduced from 40.58 ± 3.98 to 21.13 ± 6.27 min (P < 0.02), while steady state flux increased from 0.24 ± 0.03 to 0.75 ± 0.06 μg/cm2 per min (P < 0.0001). Under active occlusion, the relative change in epidermal thickness as determined by optical coherence tomography increased by 16 and 11% at 30 and 60 min, respectively.

Conclusions

Administration with a novel magnetic film array technology provided enhanced skin penetration of urea and increased epidermal hydration when compared with administration under an occlusive film only.
Electroosmotic transport of mannitol across human nail during constant current iontophoresis
Authors: Dutet Julie , Delgado-Charro M Begoña
Published: September 2015

Objectives

This work aimed to elucidate the role of electroosmosis during trans-nail iontophoresis.

Methods

Passive and iontophoretic experiments were performed after short hydration (10–15 min) of human nail tips. The electroosmotic fluxes of mannitol were determined during anodal and cathodal iontophoresis and at different pH values. Passive controls were also carried out. Four sets of experiments were performed: (a) three anodal delivery experiments using different nails, at pH 4.0, 5.0 and 7.4, (b) one anodal delivery experiment that kept the same nails across two pH stages, (c) one experiment, comprising an anodal delivery stage (pH 4 and 7.4) followed by a cathodal delivery stage (pH 7.4 and 4), which kept the same nails across the different polarities and pH stages, and (d) a passive experiment keeping the same nails across different pH values (4 and 7.4).

Results

The fluxes of mannitol measured were very variable and little difference between passive and electroosmotic transport was observed. Cathodal and anodal fluxes were not always significantly different. Experiments which minimised internail variability suggested that the nails were negatively charged at physiological pH, and that this negative charge was lost at pH 4.

Conclusions

These results suggest a modest and highly variable contribution of electroosmosis to the iontophoretic transungual flux.
Effect of a novel penetration enhancer on the ungual permeation of two antifungal agents
Authors: Traynor M J , Turner R B , Evans C R G , Khengar R H , Jones S A , Brown M B
Published: September 2015

Objectives

The aim of this study was to demonstrate the effect of a novel permeation enhancer system using two existing marketed nail lacquers and the delivery of terbinafine through human nail samples in vitro.

Methods

Initially a modified Franz cell was used, where sections of human nail serve as the barrier through which drug penetrates into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes are incubated with and grow into human nail and ATP levels are used as biological marker for antimicrobial activity.

Key findings

The novel permeation enhancing system increased the permeation of both existing drugs formulated in nail lacquers and terbinafine through human nail sections mounted in a modified Franz cell. Furthermore the ATP assay confirmed that the system also enhanced the permeation of terbinafine through infected cadaver nail resulting in a decrease in ATP levels equivalent to those of uninfected negative control samples.

Conclusions

This study has clearly demonstrated that the use of a novel permeation enhancing system, which fundamentally alters the chemical structure of the nail, not only enhances the efficacy of the existing topical formulations but also enables the delivery and efficacy of terbinafine when applied ungually. Such a topically applied system has the possibility of overcoming the systemic side effects when terbinafine is delivered orally.
The application of feature selection to the development of Gaussian process models for percutaneous absorption
Authors: Lam Lun Tak , Sun Yi , Davey Neil , Adams Rod , Prapopoulou Maria , Brown Marc B , Moss Gary P
Published: September 2015

Objectives

The aim was to employ Gaussian processes to assess mathematically the nature of a skin permeability dataset and to employ these methods, particularly feature selection, to determine the key physicochemical descriptors which exert the most significant influence on percutaneous absorption, and to compare such models with established existing models.

Methods

Gaussian processes, including automatic relevance detection (GPRARD) methods, were employed to develop models of percutaneous absorption that identified key physicochemical descriptors of percutaneous absorption. Using MatLab software, the statistical performance of these models was compared with single linear networks (SLN) and quantitative structure–permeability relationships (QSPRs). Feature selection methods were used to examine in more detail the physicochemical parameters used in this study. A range of statistical measures to determine model quality were used.

Key findings

The inherently nonlinear nature of the skin data set was confirmed. The Gaussian process regression (GPR) methods yielded predictive models that offered statistically significant improvements over SLN and QSPR models with regard to predictivity (where the rank order was: GPR > SLN > QSPR). Feature selection analysis determined that the best GPR models were those that contained log P, melting point and the number of hydrogen bond donor groups as significant descriptors. Further statistical analysis also found that great synergy existed between certain parameters. It suggested that a number of the descriptors employed were effectively interchangeable, thus questioning the use of models where discrete variables are output, usually in the form of an equation.

Conclusions

The use of a nonlinear GPR method produced models with significantly improved predictivity, compared with SLN or QSPR models. Feature selection methods were able to provide important mechanistic information. However, it was also shown that significant synergy existed between certain parameters, and as such it was possible to interchange certain descriptors (i.e. molecular weight and melting point) without incurring a loss of model quality. Such synergy suggested that a model constructed from discrete terms in an equation may not be the most appropriate way of representing mechanistic understandings of skin absorption.
The application of molecular structural predictors of intestinal absorption to screening of compounds for transdermal penetration
Authors: Grice Jeffrey E , Cross Sheree E , Brownlie Craig , Roberts Michael S
Published: September 2015

Objectives

The development of methods to predict the transport of molecules across biological membranes, without the need for time-consuming collection of experimental data, is a rapidly growing science. The use of structural characteristics of molecules has been investigated to predict the maximum transport rates of molecules across skin epidermal and intestinal membranes, known as maximum flux and maximum absorbable dose, respectively, although different approaches have been used. The aim of the present study was to determine whether the relationship between polar surface area and number of rotatable bonds of molecules and their permeability through intestinal membranes could be applied to the permeation of solutes through the epidermis following topical application.

Methods

We used a published dataset of human epidermal maximum flux values for 182 solutes and stepwise regression to determine relationships between structural predictors and maximum membrane transport rates.

Key findings

Results showed that diffusion processes occurring across intestinal and skin epidermal membranes cannot be estimated by the same solute molecular properties, as different combinations of partitioning and diffusion processes appear to be dominating in each type of membrane. The basis of these differences in terms of molecular weight dependence and the usefulness of polar surface area are discussed.

Conclusions

Based on available literature, we concluded that transdermal penetration is poorly predicted by parameters derived from intestinal or Caco-2 model membranes. While this approach may be useful for small sets of structurally related compounds, it appears to have limited value for screening and selection of novel structures in the pharmaceutical industry.
Tocopheryl acetate disposition in porcine and human skin when administered using lipid nanocarriers
Authors: Moddaresi Mojgan , Brown Marc B , Tamburic Slobodanka , Jones Stuart A
Published: September 2015

Objectives

Assessing the delivery of a drug into the skin when it has been formulated within a nanocarrier is a complex process that does not conform to the conventions of traditional semi-solid formulations. The aim of this study was to gain a fundamental understanding of drug disposition in both human and porcine skin when applied using a lipidic nanocarrier.

Methods

A model system was generated by loading tocopheryl acetate into a well-characterised solid lipid nanoparticle and formulating this system as a traditional aqueous hyaluronic acid gel. Franz diffusion cells fitted with a silicone or nylon membrane were used to assess drug and particle transport independently whilst human and pig skin were employed to determine skin delivery.

Key findings

The tocopheryl acetate, when loaded into the solid lipid nanoparticles, did not release from the particle. However, 1.65 ± 0.90% of an infinite dose of tocopheryl acetate penetrated into the stratum corneum of pig skin when delivered using a nanoparticle-containing gel.

Conclusions

These results suggest that hydration of the stratum corneum in pig skin could lead to the opening of hydrophilic pores big enough for 50 nm-sized particles to pass into the superficial layers of the skin, a phenomenon that was not repeated in human skin.
Evaluation of the effect of topical agents on radiation-induced skin disease by reflectance spectrophotometry
Authors: Rizza Luisa , D'Agostino Antonio , Girlando Andrea , Puglia Carmelo
Published: September 2015

Objectives

Radiotherapy may cause severe skin changes that significantly interfere with the patient's quality of life and reduce radiotherapy effectiveness. Many skin care instructions and various topical agents are recommended to help patients in the management of radiation skin reactions, but evidence to support the value of the topical treatments of the irradiated skin is lacking. In the present study we investigated the effects of topical agents used as supportive care to minimise radiation-induced skin disease using an instrumental method.

Methods

Subjects who were undergoing a planned course of radiation therapy after breast-conserving surgery were randomised to treatment (using one of two topical agents) or non-treatment (control) groups and monitored over 8 weeks. The intensity of skin erythema was evaluated once per week by non-invasive instrumental reflectance spectrophotometry in comparison with a visual scoring system.

Key findings

Examination of the erythema time course by a sensitive spectrophotometric reflectance method showed a significant increase of skin reactions in the non-treated group after the second week of treatment and maximal alterations between the fourth and sixth week.

Conclusions

From the results obtained, we observed that application of topical agents used in radio-induced skin disease were able to significantly reduce the erythema extent compared to the non-treated group.
Scientific evidence for Mikania laevigata and Mikania glomerata as a pharmacological tool
Authors: Napimoga Marcelo H , Yatsuda Regiane
Published: September 2015

Objectives

Historically, the majority of new drugs have been generated from natural products as well as from compounds derived from natural products. In this context, Mikania laevigata and M. glomerata, popularly known as ‘guaco’, have a long history of use. Brazilian Indians have an ancient tradition of using ‘guaco’ for snakebites. In current herbal medicine in Brazil, ‘guaco’ is used as an effective natural bronchodilator, expectorant and cough suppressant employed for all types of upper respiratory problems including bronchitis, pleurisy, colds and flu, coughs and asthma.

Key findings

In Brazil, this plant has been widely used, even as commercial preparations. Its medicinal properties are widely recognized, mainly in the treatment of inflammatory conditions, bronchodilator activity, anti-ulcerogenic, antiophidian as well as antibacterial and antiparasitic activity, although the efficacy of the antibacterial activity is so far controversial.

The studies on Mikania glomerata and M. laevigata have provided scientific evidence that those plants have a considerable anti-inflammatory therapeutic potential.