bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Protective Effect of a Water-In-Oil Microemulsion Incorporating Quercetin Against UVB-Induced Damage in Hairless Mice Skin
Authors: Vicentini Fabiana T. M. C. , Fonseca Yris M. , Pitol Dimitrius L. , Iyomasa Mamie M. , Bentley M. Vitória L. B. , Fonseca Maria J.V. 
Published: March 2016

Purpose: In the present study, histological aspects were considered in order to evaluate the in vivo photoprotective effect of a w/o microemulsion containing quercetin against UVB irradiation-induced dermal damages. The toxicity in cell culture and the potential skin irritation resulting from topical application of this formulation were also investigated. Methods: Mouse dorsal surfaces were treated topically with 300 mg of the unloaded and quercetin-loaded (0.3%, w/w) microemulsions before and after exposure to UVB (2.87 J/cm2) irradiation. The untreated control groups irradiated and non-irradiated were also evaluated. UVB-induced histopathological changes as well as the photoprotective effect of this formulation were evaluated considering the parameters of infiltration of inflammatory cells, epidermis thickening (basale and spinosum layers) and collagen and elastic fiber contents. The cytotoxicity of the reported formulation was evaluated in L929 mice fibroblasts by MTT assay and the skin irritation was investigated after topical application of both unloaded and quercetin-loaded microemulsions once a day for 15 days.
Results: The results demonstrated that the w/o microemulsion containing quercetin reduced the incidence of histological skin alterations, mainly the connective-tissue damage, induced by exposure to UVB irradiation, this allows the suggestion that protective effects of this formulation against UV-induced responses are not secondary to the interference of UV transmission (i.e., blocking the UVB radiation from being absorbed by the skin), as is usually done with UVB absorbers and sunscreens, but is instead due to different biological effects of this flavonoid. Furthermore, by evaluating the cytotoxic effect on L929 cells and histological aspects such as infiltration of inflammatory cells and epidermis thickness of hairless mice, the present study also demonstrated no toxicity of the proposed system. Conclusion: Therefore, based on these mouse models, a detailed characterization of the w/o microemulsion incorporating quercetin effects as a photochemoprotective agent on human skin is thus indicated.
Subsequent Entry Biologics in Canada: Current State of the Science
Authors: Endrenyi Laszlo , Jamali Fakhreddin , Loebenberg Raimar 
Published: March 2016

The Canadian Society for Pharmaceutical Sciences organized a workshop on the current state of sciences of subsequent entry biologics (SEBs, biosimilars) on December 10th 2014 in the Health Canada location in Ottawa, ON. The day-long workshop provided an opportunity to discuss recent regulatory developments and a wide range of scientific issues related to SEBs. Following a discussion on the differences between the Canadian guidance and those of other countries, a series of presentations were made that focused on the regulatory requirements with regard to the product quality, methodology, non-clinical and clinical data. In addition, issues of extrapolation from one indication to another, interchangeability and reimbursement were articulated. It was also highlighted that both the patients and caregivers need to be better informed regarding the safety and efficacy of articulated SEBs.
The Success Rate of New Drug Development in Clinical Trials: Crohn’s Disease
Authors: Parker Jayson Lee , Clare Kohler Jillian 
Published: March 2016

Purpose. To determine the risk of drug failure during clinical trial testing in Crohn’s disease and determine what steps can be taken to improve outcomes. This is the first study to quantify such risk for a single disease.
Methods. Moderate to severe Crohn’s disease was investigated by reviewing press releases from 1998 to June 2008. Clinical trial failure causes were classified as commercial or clinical and compared with industry expectations. The risk of failure was also reviewed based on whether the compound was a small molecule drug or a biologic. Lastly, the role of the sponsor was examined, in determining whether the size of the firm involved in a drug program was predictive of the outcome of the study.
Results. More than a120 press releases were reviewed yielding 37 drugs that met our search criteria. The cumulative success rate for drug development in Crohn’s disease is 19%, from start to finish of clinical trial testing. New drug approvals are dominated by protein based therapeutics in this indication. Commercial and clinical failures both contributed substantially to the failure rates of new drugs. Phase I clinical testing appeared to offer little risk mitigation with pass rates at 95%.
Conclusion. Funding intended to advance Crohn’s disease must take into account the disease specific historical failure rate of drug development in forecasting any reasonable expectation of producing new therapies. As it currently stands, one in five drugs will be successfully approved that enter clinical trial testing in this indication. To manage this risk continued development of biologics over small molecule drugs may be warranted in this disease.
Prediction of In Vivo Atenolol Removal by High-Permeability Hemodialysis Based on an In Vitro Model
Authors: Daheb Kahina , Lecours Jean-Philippe , Lipman Mark L. , Hildgen Patrice , Roy Julie J. 
Published: March 2016

Purpose. In order to update our data on drug dialyzability using the high-permeability dialysis membranes, atenolol elimination by an in vitro dialysis model was compared to that observed in six patients during high-permeability hemodialysis (HD), and the predictive value of the model was evaluated. Methods. Atenolol clearance was evaluated in six patients undergoing chronic HD. They were considered as eligible candidates if they were between 18 and 80 years of age, had a body mass index between 19 and 30 kg/m2, underwent HD and were taking atenolol on a regular basis in oral tablet form for at least 1 month before the study started. Atenolol clearance was also evaluated in three in vitro dialysis sessions with high-permeability polysulfone membrane. Atenolol was dissolved in 6 L of Krebs-Henseleit buffer with bovine serum albumin. Dialysis parameters were set to mirror as much as possible the patients’ parameters (flow rate: 300 mL/min, dialyzate flow: 500 mL/min). After sample collection, drug concentrations were measured with high performance liquid chromatography. The comparison between in vivo and in vitro atenolol elimination kinetics was performed by drawing the curve fittings of concentrations vs. time on SigmaPlot 12, and adding a 95% prediction interval to each elimination curve fitting. Results. Mean dialysis clearance of atenolol in vitro and in vivo was 198 ± 4 and 235 ± 53 mL/min, respectively. Atenolol was significantly removed within the study time period in both in vitro and in vivo experiments. By the end of in vitro dialysis, atenolol remaining in the drug reservoir was less than 2% of initial arterial concentration. Conclusion. Our study has indicated that atenolol is almost entirely cleared during high-permeability hemodialysis. Furthermore, the in vitro prediction interval of the drug elimination curve fitting could forecast its in vivo elimination especially at the end of dialysis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Role of Two Efflux Proteins, ABCB1 and ABCG2 in Blood-Brain Barrier Transport of Bromocriptine in a Murine Model of MPTP-Induced Dopaminergic Degeneration
Authors: Vautier Sarah , Milane Aline , Fernandez Christine , Chacun Helene , Lacomblez Lucette , Farinotti Robert 
Published: March 2016

Purpose: MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson’s disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported.
Methods: We have investigated the transport of bromocriptine through the blood-brain barrier (BBB) in a MPTP model to understand the influence of the dopaminergic degeneration on ABCB1 and ABCG2.
Results: We have shown that in MPTP treated mice, bromocriptine is widely distributed to brain (2.3-fold versus control, p
The Lidose Hard Capsule Formulation of Fenofibrate is Suprabioavailable Compared to the Nanoparticle Tablet Formulation Under High-fat Fed Conditions
Authors: Verbeeck Roger K , Niet Sophie De , Lebrun Sonia , Tremege Mickael , Rennie Tim W. , Coffiner Monte , Streel Bruno , Cahay Bernard 
Published: March 2016

Purpose: The therapeutic equivalence of multiple registered fenofibrate formulations, several of which are suprabioavailable and therefore marketed at lower dosage strengths than their reference products, is based on the results of bioequivalence studies. Most of these formulations show a higher bioavailability when taken with a high-fat meal. The relative bioavailability of two of these formulations, the 200 mg Lidose hard capsules and the 145 mg nanoparticle tablets, was assessed when taken with a high-fat meal. Methods: In this single dose, 2-way, randomized, crossover study, 24 healthy subjects received a 200 mg fenofibrate Lidose hard capsule (Test) and a 145 mg nanoparticle tablet (Reference) under high-fat fed conditions. Plasma concentrations of fenofibric acid were measured up to 72 hours by using a validated LC-MS/MS method. Results: The geometric mean ratios (Test/Reference) and the 90% confidence intervals for AUC0-t and Cmax were 1.37 (131.58 – 142.88) and 1.38 (124.60 – 152.93), respectively. The median (range) Tmax­ values of fenofibric acid were 4.5 h (3.0 – 8.0 h) and 3.25 h (1.0 – 6.5 h) after administration of the Lidose hard capsule and the nanoparticle tablet, respectively. Conclusion: Under high-fat fed conditions the extent of fenofibrate absorption was 37% higher for the 200 mg Lidose hard capsule compared to the 145 mg nanoparticle tablet, which is exactly as expected based on a mg-to-mg weight basis. The results of the present study underline the importance of assessing bioequivalence of fenofibrate formulations under identical fed conditions, and preferentially after a high-fat meal as this condition represents the worst-case scenario. Furthermore, the results of this study demonstrate that the 145 mg nanoparticle tablet is not bioequivalent to the 200 mg Lidose hard capsule when administered under high-fat meal conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Diabetes Results in Structural Alteration of Chondroitin Sulfate in the Urine
Authors: Zhao Tingting , Lu Xiaoguang , Davies Neal M , Gong Yuewen , Guo Jingzhen , Zhang Haojun , Li Zhiguo , Hong Jing , Fu Guixiang , Li Ping 
Published: March 2016

Purpose. The assessment of the clinical significance of chondroitin sulfate in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) for the detection of the relationship between chondroitin sulfate (CS) structure and disease. Methods. Healthy control (n=15), type 2 diabetic patients with normalbuminuria (n=12), and patients with microalbuminuria (n=13) were enrolled in the study. Total sulfated glycosaminoglycans (GAGs) concentration in the first morning urine was evaluated by 1,9-dimethylmethylene blue method and the composition was determined by agarose gel electrophoresis. Urinary chondroitin sulfate was quantified by a combination of treatment with specific lyase digestions and separation of products by SAX-HPLC. Results: GAGs concentration significantly increased in diabetic patients with microalbuminuria compared to diabetic patients with normalbuminuria. Qualitative analysis of urinary GAGs revealed the presence of chondroitin sulfate, heparan sulfate, and low-sulphated chondroitin sulphate-protein complex (LSC-PG). There was a decrease in CS and an increase in LSC-PG in the urine of patients with diabetes compared to healthy controls. Moreover, in diabetic patients, chondroitin sulfate contains more 6-sulfated disaccharide and less 4-sulfated disaccharide. There was a statistically significant difference in ratio of 6-sulfated disaccharide to 4-sulfated disaccharide among the three groups. Conclusions: GAGs were significantly increased in diabetic patients with microalbuminuria. The levels of urinary GAGs, ratio of LSC-PG/CS, as well as ratio of 6-sulfated to 4-sulfated disaccharides could be useful markers for diagnosis of patients with diabetic nephropathy. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Clinical Trial Risk in Type-2 Diabetes: Importance of Patient History
Authors: Aiyere Emmanuel O. , Silverberg Jay , Ali Safina , Parker Jayson L. 
Published: March 2016

Purpose. To determine the risk of clinical trial failure for drugs developed for type-2 diabetes. Methods. Drugs were investigated by reviewing phase I to phase III studies that were conducted between 1998 and February 2013. The clinical trial success rates were calculated and compared to the industry standard. The drugs were classified into GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors and “Other”. The exclusion criteria for drugs in this study: Drugs that were started in phase I studies prior to January 1998 for this indication and drugs whose primary indications were not for the control of blood glucose levels. Results. Data was extracted from clinicaltrials.gov; there were a total of 131 drug candidates that fit our specified criteria, of which 8 received FDA approval. The cumulative success rate for molecules developed for type-2 diabetes is 10%. Small molecules were more successful than biologics. A strong disparity was observed in phase III, with studies that utilised treatment naïve patients having a 40% success rate, compared to an 83% success rate in patients who have had previous anti-hyperglycemic exposure. Conclusions. 1 in 10 drugs that enter clinical testing in this disease will be approved. The DPP-4 inhibitor class of drugs had the highest success rate of all drug classes with a 63% cumulative success rate; while treatment naïve patients carried the greatest clinical trial risk. Keywords: Clinical trials, Type-2 diabetes, Drug development, Clinical trial risk. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Design Space Approach for Preservative System Optimization of an Anti-Aging Eye Fluid Emulsion
Authors: Lourenço Felipe Rebello , Francisco Fabiane Lacerda , Ferreira Márcia Regina Spuri , Andreoli Terezinha De Jesus , Löbenberg Raimar , Bou-Chacra Nádia 
Published: March 2016

The use of preservatives must be optimized in order to ensure the efficacy of an antimicrobial system as well as the product safety. Despite the wide variety of preservatives, the synergistic or antagonistic effects of their combinations are not well established and it is still an issue in the development of pharmaceutical and cosmetic products. The purpose of this paper was to establish a space design using a simplex-centroid approach to achieve the lowest effective concentration of 3 preservatives (methylparaben, propylparaben, and imidazolidinyl urea) and EDTA for an emulsion cosmetic product. Twenty-two formulae of emulsion differing only by imidazolidinyl urea (A: 0.00 to 0.30% w/w), methylparaben (B: 0.00 to 0.20% w/w), propylparaben (C: 0.00 to 0.10% w/w) and EDTA (D: 0.00 to 0.10% w/w) concentrations were prepared. They were tested alone and in binary, ternary and quaternary combinations. Aliquots of these formulae were inoculated with several microorganisms. An electrochemical method was used to determine microbial burden immediately after inoculation and after 2, 4, 8, 12, 24, 48, and 168 h. An optimization strategy was used to obtain the concentrations of preservatives and EDTA resulting in a most effective preservative system of all microorganisms simultaneously. The use of preservatives and EDTA in combination has the advantage of exhibiting a potential synergistic effect against a wider spectrum of microorganisms. Based on graphic and optimization strategies, we proposed a new formula containing a quaternary combination (A: 55%; B: 30%; C: 5% and D: 10% w/w), which complies with the specification of a conventional challenge test. A design space approach was successfully employed in the optimization of concentrations of preservatives and EDTA in an emulsion cosmetic product. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Hyaluronic Acid and Wound Healing
Authors: Neuman Manuela G , Nanau Radu M , Oruña-Sanchez Loida , Coto Gabriel 
Published: March 2016

Background. We developed an experimental model of ethanol-induced dermatotoxicity and hepatocytoxicity using normal human keratinocytes and normal human hepatocytes that preserve inducible cytochrome p450 activities. The original work was described in several articles. The objective of this study was to determine whether hyaluronic acid attenuates skin necrosis, and to further clarify its uses in wound repair in humans, animal models and in vitro studies. Methods. We performed a systematic review of the literature using the terms “hyaluronic acid” and “wound healing”. PubMed was searched for studies published during the period 2010-2014. Results. Hyaluronic acid is used in tissue regeneration alone or in combination with herbal or Western medicine. Scaffolds made up of hyaluronic acid were used to embed basic fibroblast growth factor. Conclusion. Hyaluronic acid extracts are safe and efficacious products to be used in skin repair. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Inhibition of Human Cytochrome P450 Metabolism by Blended Herbal Products and Vitamins
Authors: Tam Teresa W , Akhtar Humayoun , Arnason John Thor , Cvijovic Kosta , Boon Heather , Cameron D William , Drouin Cathy E , Jaeger Walter , Tsuyuki Ross T , Vohra Sunita , Foster Brian C 
Published: March 2016

Purpose. The use of supplements as herbal and micronutrient natural health products with conventional health products has become increasingly popular. It has been reported that some herbal products can inhibit the activity of cytochrome P450-mediated metabolism and drug disposition. This study was designed to investigate a case report of a severe adverse event to determine the potential interactions of femMED, Thyrosense and vitamins on cytochrome P450-mediated drug metabolism.
Methods. The effect of extracts from these commercially available herbal formulations, trans-ß-carotene, multivitamins, and vitamin D3 supplements on cytochrome P450-mediated drug metabolism of marker substrates was determined in vitro.
Results. The blended herbal products femMED and Thyrosense had a high potential to affect the safety and efficacy of many health products. Some vitamin and trans-β-carotene containing products also have the potential to affect drug disposition. The ß-carotene content of various products was analyzed and significant discrepancies were found among them and between values indicated on product labels. Product extracts also exhibited a low to moderate capacity to inhibit cytochrome P450 2C9, 2C19 and 3A4-mediated metabolism.
Conclusions. The findings of this study suggest that these herbal products and most vitamin products may have an inhibitory effect on cytochrome P450 activity that could contribute to development of an adverse event. Further work is warranted to determine how supplementation with these products may affect drug metabolism in an in vivo context.
Puerarin Suppresses Angiotensin II-Induced Cardiac Hypertrophy by Inhibiting NADPH Oxidase Activation and Oxidative Stress-Triggered AP-1 Signaling Pathways
Authors: Gang Chen , Qiang Cao , Xiangli Cui , Shifen Pan , Chong Shen , Lihong Liu 
Published: March 2016

PURPOSE. To examine the effects of puerarin (Pue) on angiotensin II (AngII)-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and oxidative stress-related signaling pathways in the hypertrophic response of cardiomyocytes. METHODS. Primary cardiomyocytes of neonatal C57BL/6J mice were pretreated with Pue (50, 100 μmol/L) and were then stimulated with AngII 1 μmol/L. NADPH oxidase activity and reactive oxygen species (ROS) levels were measured by lucigenin-enhanced chemiluminescence assay and flow cytometry. Western blotting was used to detect the distribution of the oxidase subunits, extracellular signal-regulated kinase (ERK1/2) and c-jun N-terminal kinase (JNK1/2) activation, and an electrophoretic mobility shift assay (EMSA) was performed to analyze the DNA binding activity of activator protein-1 (AP-1). Adult C57BL/6J mice were infused with AngII and were administered with Pue (100, 200 mg·kg-1·d-1) for 15 d. After the treatment, systolic blood pressure (SBP) and left ventricular wall thickness were examined. The ratios of heart weight to body weight (HW/BW) and left ventricular weight to body weight (LVW/BW) were measured, and heart morphometry was assessed. RESULTS. In vitro, Pue dose-dependently blocked the phosphorylation of ERK1/2 and JNK1/2 and eventually abolished AP-1 binding activity through the inhibition of ROS production. Further studies revealed that AngII treatment resulted in increased NADPH oxidase activity, which was suppressed by Pue via the disruption of Rac1 activation and membrane translocation of oxidase subunits. In vivo, Pue attenuated cardiac hypertrophy, as evaluated by decreased HW/BW, LVW/BW, myocyte surface area, and left ventricular wall thickness. CONCLUSIONS. The anti-hypertrophic mechanism of Pue occurred by blocking Rac1-dependent NADPH oxidase activation and downstream redox-sensitive AP-1 signaling pathways. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Supercritical Fluid Technologies to Fabricate Proliposomes
Authors: Falconer James R. , Svirskis Darren , Adil Ali A. , Wu Zimei 
Published: March 2016

Proliposomes are stable drug carrier systems designed to form liposomes upon addition of an aqueous phase. In this review, current trends in the use of supercritical fluid (SCF) technologies to prepare proliposomes are discussed. SCF methods are used in pharmaceutical research and industry to address limitations associated with conventional methods of pro/liposome fabrication. The SCF solvent methods of proliposome preparation are eco-friendly (known as green technology) and, along with the SCF anti-solvent methods, could be advantageous over conventional methods; enabling better design of particle morphology (size and shape). The major hurdles of SCF methods include poor scalability to industrial manufacturing which may result in variable particle characteristics. In the case of SCF anti-solvent methods, another hurdle is the reliance on organic solvents. However, the amount of solvent required is typically less than that used by the conventional methods. Another hurdle is that most of the SCF methods used have complicated manufacturing processes, although once the setup has been completed, SCF technologies offer a single-step process in the preparation of proliposomes compared to the multiple steps required by many other methods. Furthermore, there is limited research into how proliposomes will be converted into liposomes for the end-user, and how such a product can be prepared reproducibly in terms of vesicle size and drug loading. These hurdles must be overcome and with more research, SCF methods, especially where the SCF acts as a solvent, have the potential to offer a strong alternative to the conventional methods to prepare proliposomes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.