bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Surface Tension in Pharmaceutical Sciences
Authors: Fathi Azarbayjani Anahita , Jouyban Abolghasem , Chan Sui Yung
Published: March 2016

Surface chemistry has a large influence in many industries. In the life sciences, surface area is gaining importance in the characterization of materials during their development, formulation and manufacturing. The chemical activity, adsorption, dissolution, and bioavailability of a drug may depend on the surface of the molecule. In order to meet manufacturing challenges and develop new and better performing products with improved qualities, knowledge of surface tension is of utmost importance. An attempt has been made in this paper to review the application of interfacial tension in the key domains of pharmaceutical applications.
A Systematic Review of in vitro Studies Conducted on Effect of Herbal Products on Secretion of Insulin from Langerhans Islets
Authors: Abdollahi Mohammad , Tabatabaei-Malazy Ozra , Larijani Bagher
Published: March 2016

Purpose: Diabetes mellitus is the most important health problem that its prevalence is increasing. Diabetes is characterized by defects in insulin secretion, insulin action or both. Recent studies provided evidences that loss of functional β-cell mass through apoptosis is central to the development of diabetes. The management of diabetes without any side effects is still a challenge to the medical system. Recently, there has been a special interest to herbal medicine in care and management of diabetes due to their natural origin and less side effects. The current systematic review focuses on main component of antidiabetic plants with directly effect on insulin secretion of pancreas. Methods: All in vitro studies which assessed the potential effect of, main components, multi herbal, whole plant, or extract of the plants directly on pancreatic insulin secretion published from 2001 to November 2011 were included. Exclusion criteria were clinical trial studies that did not assess insulin secretion, and review articles, or letters to the editor. Results: The majority of these studies showed that the improvement of β-cell function and insulin secretion is possible with antioxidant compounds. Suppression of oxidative stress, cytokine-induced impairment, suppression of nuclear factor κB a key regulator of endothelial activation, activation of uncoupling protein 2 (UCP2), insulin-like activity and increasing intracellular calcium, were among the most important indicated pathways. Conclusions: By considering the role of oxidative stress in pathogenesis of β-cell dysfunction, antioxidant compounds could be helpful in management of diabetes and its complications.
Impact of Erythrocyte Duffy Antigen Genetic Polymorphism on the Distribution of GroB-T, a Novel Human CXC Chemokine
Authors: Hepburn Timothy W , Tobia LeeAnn P , Shi Wei , McIntyre Timothy A , Davis Charles B
Published: March 2016

Purpose. GroB-T, a human CXC chemokine, has been studied for its potential to mobilize stem cells. Chemokines bind specifically to receptors on target immune cells but also to a homologous erythrocyte blood group antigen, the Duffy Antigen/Receptor for Chemokines (DARC) that is subject to genetic polymorphism in humans. A mutation in the DARC gene is common among African Americans and results in lack of expression of the erythrocyte antigen. We used a combination of in vitro studies of GroB-DARC interaction and pharmacokinetic simulation to anticipate the potential impact of this polymorphism on the pharmacokinetics of GroB-T. Methods. [125I]GroB-T was incubated in Caucasian blood to characterize the concentration dependence of the blood to plasma concentration ratio (B/P). Affinity and capacity of binding was estimated by Scatchard analysis; specificity was investigated by competitive displacement with a CC chemokine. The B/P value (7 nM) was then determined in blood from 8 African American subjects. Duffy antigen expression was determined by antibody agglutination. A pharmacokinetic model was developed which accounted for blood-cell binding. Simulations were performed to explore effects of dose regimen and DARC expression on the GroB-T plasma concentration-time profile. Results. GroB-T affinity and capacity for DARC (Caucasian blood) were 23.0 +/- 1.2 and 37.7 +/- 0.6 nM, respectively; excess CC chemokine fully displaced [125I]GroB-T. Chemokine binding was highly correlated with the presence or absence of the Duffy antigen (p
Overview of Plant-Derived Vaccine Antigens: Dengue Virus
Authors: Malabadi Ravindra B , Ganguly Advaita , Teixeira da Silva Jaime A , Parashar Archana , Suresh Mavanur R , Sunwoo Hoon
Published: March 2016

ABSTRACT - This review highlights the advantages and current status of plant-derived vaccine development with special reference to the dengue virus. There are numerous problems involved in dengue vaccine development, and there is no vaccine against all four dengue serotypes. Dengue vaccine development using traditional approaches has not been satisfactory in terms of inducing neutralizing antibodies. Recently, these issues were addressed by showing a very good response to inducing neutralizing antibodies by plant-derived dengue vaccine antigens. This indicates the feasibility of using plant-derived vaccine antigens as a low-cost method to combat dengue and other infectious diseases. The application of new methods and strategies such as dendritic cell targeting in cancer therapy, severe acute respiratory syndrome, tuberculosis, human immune deficiency virus, and malaria might play an important role. These new methods are more efficient than traditional protocols. It is expected that in the near future, plant-derived vaccine antigens or antibodies will play an important role in the control of human infectious diseases.

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.
Use of Proton Pump Inhibitors as Adjunct Treatment for Triple-Negative Breast Cancers. An Introductory Study
Authors: Goh Wayne , Sleptsova-Freidrich Inna , Petrovic Nenad
Published: March 2016

PURPOSE: Triple negative breast cancers (estrogen, progesterone and human epidermal growth factor 2 (HER2) receptor-negative) are among the most aggressive forms of cancers with limited treatment options. Doxorubicin is one of the agents found in many of the current cancer treatment protocols, although its use is limited by dose-dependent cardiotoxicity. This work investigates one of the ways to suppress cancer growth by inhibiting tumor cell ability to remove acid accumulated during its metabolism by proton pump inhibitor esomeprazole (a drug with extensive clinical use) which could serve as an addition to doxorubicin therapy. METHODS: In this work, we have investigated growth suppression of triple-negative breast cancer cells MDA-MB-468 by esomeprazole and doxorubicin by trypan blue exclusion assay. Measurement of acidification of treated cancer cells was performed using intracellular pH-sensitive probe, BCECF-AM. Finally, expression of gastric type proton pump (H+/K+ ATPase, a target for esomeprazole) on MDA-MB-468 cells was detected by immunofluorescence and Western blotting. RESULTS: We have found that esomeprazole suppresses growth of triple-negative breast cancer cell in vitro in a dose-dependent manner through increase in their intracellular acidification. In contrast, esomeprazole did not have significant effect on non-cancerous breast epithelial MCF-10A cells. Esomeprazole increases doxorubicin effects suggesting that dual treatments might be possible. In addition, response of MDA-MB-468 cells to esomeprazole could be mediated by gastric type proton pump (H+/K+ ATPase) in cancer cells contrary to previous beliefs that this proton pump expression is restricted to parietal cells of the stomach epithelia. CONCLUSION: This study provides first evidence that adjunct use of esomeprazole in breast cancer treatment might be a possible to combat adverse effects of doxorubicin and increase its effectiveness. 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.
Influence of Oleic Acid on the Rheology and in Vitro Release of Lumiracoxib from Poloxamer Gels
Authors: Moreira Tailane Sant´Anna , De Sousa Valéria Pereira , Pierre Maria Bernadete Riemma
Published: March 2016

Abstract

PURPOSE: Transdermal delivery of anti-inflammatory lumiracoxib (LM) could be an interesting strategy to avoid the side effects associated with systemic delivery, but it is ineffective due to the drug poor skin penetration. We have investigated the effects of oleic acid (OA), a lipid penetration enhancer, on the in vitro release of LM from poloxamer-based delivery systems (PBDS). The rheological behavior (shear rate dependent viscosity) and gelation temperature through measurements of optimal sol-gel transition temperatures (Tsol-gel) were also carried out in these systems. METHODS: In vitro release studies of LM from PBDS were performed using cellulose acetate as artificial membrane mounted in a diffusion system. The amount of LM released was divided by exposition area (µg/cm2) and these values were plotted as function of the time (h). The flux of the drug across the membrane (J) was calculated from the slope of the linear portion of the plot and expressed as µg/cm2. h -1. The determination of viscosity was carried out at different shear rates (γ) between 0.1- 1000 S-1 using a parallel plate rheometer. Oscillatory measurements using a cone-plate geometry rheometer surrounded by a double jacket with temperature varying 4-40°C, was used in order to determine Tsol-gel. RESULTS: Increase of both polymer and OA concentrations increases the viscosity of the gels and consequently reduces the in vitro LM release from the PBDS, mainly for gels containing OA at 10.0% compared to other concentrations of the penetration enhancer. Tsol-gel transition temperature was decreased by increasing viscosity; in some cases the formulation was already a gel at room temperature. Rheological studies showed a pseudoplastic behavior, which facilitates the flow and improves the spreading characteristics of the formulations. CONCLUSIONS: Taken together, the results showed that poloxamer gels are good potential delivery systems for LM, leading to a sustained release, and also have appropriate rheological characteristics.

Novelty of the work: A transdermal delivery of non-steroidal antinflammatory drugs like lumiracoxib (LM) can be an interesting alternative to the oral route of this drug, since it was recently withdraw of the market due to the liver damage when systemically administered in tablets as dosage form. There are no transdermal formulations of LM and it could be an alternative to treat inflammation caused by arthritis or arthrosis. Then, an adequate delivery system to LM is necessary in order to release the drug properly from the PBDS as well as have good characteristics related to semi-solid preparations for transdermal application, which were evaluated through in vitro release studies and rheological behavior in this paper, respectively.
Transport Characteristics of Tryptanthrin and its Inhibitory Effect on P-gp and MRP2 in Caco-2 Cells
Authors: Zhu Xingang , Zhang Xuelian , Ma Guo , Yan Junkai , Wang Honghai , Yang Qing
Published: March 2016

Purpose. Tryptanthrin, an indole quinazoline alkaloid with multiple medical activities, has been recently under preclinical development as an anti-tuberculosis and anti-tumor drug. The aims of this study are to characterize the intestinal transport of tryptanthrin in Caco-2 cells, to determine whether P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are involved in this issue, and to evaluate the potential influence of tryptanthrin on the function of P-gp and MRP2. Methods. Transport assays of tryptanthrin were performed in Caco-2 monolayers with or without the supplement of P-gp and MRP2 inhibitors. Transport assays of P-gp and MRP2 substrates were also performed in the presence of tryptanthrin. The effect of tryptanthrin on the expression of P-gp and MRP2 was analyzed by reverse transcriptase-PCR. Results. Both absorption and secretion of tryptanthrin were concentration-independent at a low concentration range of 0.8–20 µM. The apparent permeability (Papp) for the apical (AP) to basolateral (BL) was 6.138 ± 0.291 × 10-5. The ratio of Papp (BL→AP) to Papp (AP→BL) was 0.77, suggesting greater permeability in the absorptive direction. Both the P-gp inhibitor, verapamil, and the MRP2 inhibitor, glibenclamide, didn’t affect the efflux transport of tryptanthrin. The efflux transport of the P-gp substrate, digoxin, and the MRP2 substrate, pravastatin sodium, decreased when tryptanthrin was present. However, tryptanthrin didn’t change the expression of P-gp and MRP2. Conclusions. Tryptanthrin was well absorbed across the Caco-2 monolayers, and its transepithelial transports were dominated by passive diffusion. Tryptanthrin was not a substrate, but a potential inhibitor of P-gp and MRP2.

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Examining the Role of Metabolites in Bioequivalence Assessment
Authors: Karalis Vangelis , Macheras Panos
Published: March 2016

PURPOSE. Investigate the role of metabolites in bioequivalence (BE) assessment.

METHODS. Sets of ordinary differential equations are used to generate concentration - time data for both parent drug (P) and metabolite (M). The calculations include 24 subjects, two different formulations (Test, Reference), and a range of Test/Reference ratios for the fraction of dose absorbed and the rate of absorption. A summarized view of these results is made through the construction of three dimensional power curves. The criteria for the choice of the preferred analyte (P or M) are based on a sensitivity analysis of the bioequivalence measure (AUC, Cmax). The latter depends on the relative ability of P and M to reflect better the changes of the pharmacokinetic parameters and variability.

RESULTS. The different sensitivity properties of P and M were reflected on the power curves. For AUC, the performance of metabolite is very similar to that of the parent drug for all scenarios and models examined. A more complex behaviour is evident for Cmax. In most of these cases, metabolite data show higher permissiveness in the percentages of acceptance. This attribute is more evident when P exhibits high elimination rate and/or the formation of M occurs rapidly. When the Test and Reference products have similar absorption profiles, metabolite data are preferable for the determination of bioequivalence. Parent drug has the advantage for detecting better the differences in the absorption rate of two drugs. The latter is counterbalanced by the increased sensitivity of P data to the variability of the data.

CONCLUSIONS. Both parent drug and metabolite share the same ability to declare BE when AUC is used as a bioequivalence measure. In case of Cmax, metabolite data exhibit better performance when the T and R products are truly bioequivalent or the two formulations differ in their extent of absorption. Parent drug data are more sensitive to detect differences in the rate of absorption. However, in such cases, their information is much influenced by the increased variability.
Examining the cognitive effects of a special extract of Bacopa monniera (CDRI08: Keenmnd): A review of ten years of research at Swinburne University
Authors: Stough Con , Scholey Andrew , Cropley Vanessa , Wesnes Keith , Zangara Andrea , Pase Matthew , Savage Karen , Nolidin Karen , Downey Luke
Published: March 2016

Bacopa monniera (EBm), an Indian aquatic herb, has been used in traditional Ayurvedic medicine for centuries for indications related to memory and inflammation. More recently specific extracts of EBm have emerged that have been subjected to rigorous in vitro, animal and now human clinical trials. In this paper we discuss some of these studies with special reference to mechanisms and efficacy of a special extract of Bacopa (CDRI08). Studies using this extract indicate that CDRI08 has several modes of action on the human brain. Promising indications for use in humans include improving cognition in the elderly and in patients with neurodegenerative disorders.
Hepatotoxic Botanicals - An Evidence-based Systematic Review
Authors: Abdualmjid Reem J , Sergi Consolato
Published: March 2016

Purpose. Herbal medicines have been increasingly used worldwide. However, the potential harms of these herbs have been noticed most recently following hepatotoxicity with ingestion of herbal remedies. The aim of this review is to evaluate the evidence of hepatotoxic effects linked to use of herbal preparations. Method. Electronic search was performed by searching several databases: PubMed, HerbMed, Google Scholar, Scopus, Cochrane Database of Systematic Reviews and Cochrane Library using both Latin and common names of several herbs. Language was restricted to English and articles were selected for relevance reporting incidence of hepatotoxicity associated with use of herbal products in human. Results. From a total of 565 relevant reviews and articles, 254 met our inclusion criteria and were analyzed. Serious hepatotoxic events associated with various herbal products alone or in combination with other drugs have been reported. Linking to herbal constituents the spectrum of liver toxicity includes elevated liver enzymes, acute or chronic hepatitis, cholestasis, hepatic necrosis, fibrosis, and cirrhosis, as well as acute liver failure and hepatic veno-occlusive disease. Conclusion. The hepatotoxicity of herbs was extensively acknowledged. As the use of natural medicine increases, the risk of liver toxicity and drug interaction increase as well. Accordingly, herbal remedies have been known as hepatotoxins causing several liver damages. Further scientific studies with high and good quality are needed to identify toxic compounds and understand the exact mechanism of hepatotoxicity-induced by herbs. The adverse effects of herbal products must be fully reported as well as extensive education of healthcare providers must be provided in order to reduce danger of alternative medicines.

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.
Light-to-Moderate Ethanol Feeding Augments AMPK-α Phosphorylation and Attenuates SREBP-1 Expression in the Liver of Rats
Authors: Nammi Srinivas , Roufogalis Basil D
Published: March 2016

Purpose: Fatty liver disease, a hepatic manifestation of metabolic syndrome, is one of the major causes of chronic liver diseases. Epidemiological studies suggest that regular light-to-moderate ethanol consumption lowers the risk of developing metabolic disorders including dislipidemia, insulin resistance, type 2 diabetes and fatty liver disease. However, the mechanism(s) of the protective effect of light-to-moderate ethanol consumption on the liver remains unknown. Methods: In the present study, we investigated the effects of light (6%, 0.94 g/kg/day) and moderate (12%, 1.88 g/kg/day) ethanol feeding in rats for 3 weeks on the circulating and hepatic biochemical profiles and on the hepatic protein expression and phosphorylation status of adenosine monophosphate-activated protein kinase-α (AMPK-α) and other down-stream targets of this enzyme including sterol regulatory element-binding protein-1 (SREBP-1), SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase). Results: Despite no significant difference in food-intake among the groups, light ethanol treatment significantly increased the body weight compared to control rats. Serum glucose, insulin, total cholesterol, triglycerides, phospholipids and hepatic cholesterol and triglycerides were not significantly different among the groups. However, serum free fatty acids were significantly reduced with light ethanol treatment. Both light and moderate ethanol treatment significantly increased the hepatic levels of phosphorylated AMPK-α protein and this was associated with significant reduction of SREBP-1 protein expression, suggesting an enhanced fatty acid oxidation. In addition, light ethanol treatment significantly decreased the SCAP protein expression in the liver. However, liver HMG-CoA protein expression was not significantly different with ethanol consumption. Conclusion: Chronic light-to-moderate ethanol consumption increased AMPK activation which was associated with decreased expression of SREBP-1 and SCAP in the liver. Thus, our studies provide mechanistic evidence for the earlier epidemiological studies that indicate light-to-moderate ethanol intake lowers the risk of development of fatty liver disease and other metabolic disorders. Our studies demonstrate that the protective effects of light-to-moderate ethanol arise at least in part by increased phosphorylation of AMPK-α and decreased SREBP-1 expression in the liver. Further studies are warranted to determine the effects of light-to-moderate ethanol on intracellular up-stream and down-stream targets of AMPK and also on the implications of light-to-moderate ethanol in protecting non-alcoholic fatty liver disease. 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.
Development of dissolution tests for the quality control of complementary/alternate and traditional medicines: Application to African potato products
Authors: Nair Vipin Devi Prasad , Kanfer Isadore
Published: March 2016

ABSTRACT - Purpose: Unlike orthodox medicines, specific guidelines for dissolution testing of complementary/alternate (CAMs) and traditional medicines (TMs) have not been developed nor is dissolution testing a requirement for the quality control of such products. In this report, the dissolution of African Potato (AP) products, an African traditional medicine (ATM) which has been ingested by man for a diversity of ailments, has been investigated. A norlignan glycoside namely hypoxoside and a sterol, ?-sitosterol (BSS) are purported to be the most important phytochemicals in marketed products of AP. Dissolution testing of AP products containing labelled content of sterols and those containing only hypoxoside is proposed whereby BSS and hypoxoside are monitored as markers for the release of the contents of the abovementioned products, respectively. Methods: The FDA dissolution guidance for industry was used to study the best dissolution condition for several formulations of AP. Buffers in the range of pH 1.2 to 7.5 were used to investigate the dissolution of AP products containing hypoxoside as a marker compound. Similarly, biorelevant dissolution media such as fasted state simulation fluid (FaSSIF) and fed state simulation fluid (FeSSIF) at different pH were used to investigate the release of BSS in AP formulations labelled to contain sterols which exhibited poor water solubility. Results: Dissolution testing of AP products containing hypoxoside, conducted at pH 1.2 using USP Apparatus 1 indicated that more than 75% of hypoxoside was released within 1 hr. Dissolution testing of products containing sterols, conducted in FeSSIF at a pH of 5.0 resulted in a release of at least 75% of BSS after 1 hr for all but one of the products tested. Conclusions: Dissolution testing conditions have been developed for AP products containing two different marker compounds where one of the components, hypoxoside, is water soluble, whereas another component, BSS is poorly water soluble. This necessitated the use of different dissolution media and pHs in order to monitor the respective release of hypoxoside and BSS from AP products.

The results of this study indicate the necessity and possibility of developing appropriate dissolution testing procedures for use in the quality control of CAMs/TMs.
Prevalence and Predictors of Potential Drug-Drug Interactions in the Elderly: A Cross-Sectional Study in the Brazilian Primary Public Health System
Authors: Obreli Neto Paulo Roque , Nobili Alessandro , Marusic Srecko , Pilger Diogo , Guidoni Camilo Molino , Baldoni André de Oliveira , Cruciol-Souza Joice Mara , Da Cruz Alessandra Negri , Gaeti Walderez Penteado , Cuman Roberto Kenji Nakamura
Published: March 2016

Purpose. The primary objective of this study was to investigate the prevalence of clinically important potential drug-drug interactions (DDIs) in elderly patients attending the public primary health care system in Brazil. The secondary objective was to investigate possible predictors of potential DDIs. Methods. A cross-sectional study was carried out in 5 Brazilian cities located in the Ourinhos Micro-region, Sao Paulo State, between November 2010 and April 2011. The selected sample was divided according to the presence (exposed) or absence (unexposed) of one or more potential DDIs (defined as the presence of a minimum 5-day overlap in supply of an interacting drug pair). Data were collected from medical prescriptions and patients’ medical records. Potential DDIs (rated major or moderate) were identified using 4 DDI-checker programs. Logistic regression analysis was used to study potential DDI predictors. Results. The prevalence of clinically important potential DDIs found during the study period was 47.4%. Female sex (OR = 2.49 [95% CI 2.29–2.75]), diagnosis of ≥ 3 diseases (OR = 6.43 [95% CI 3.25–12.44]), and diagnosis of hypertension (OR = 1.68 [95% CI 1.23–2.41]) were associated with potential DDIs. The adjusted OR increased from 0.90 [95% CI 0.82–1.03] in patients aged 60 – 64 years to 4.03 [95% CI 3.79 – 4.28] in those aged 75 years or older. Drug therapy regimens involving ≥ 2 prescribers (OR = 1.39 [95% CI 1.17–1.67]), ≥ 3 drugs (OR = 3.21 [95% CI 2.78–3.59]), ≥ 2 ATC codes (OR = 1.19 [95% CI 1.12–1.29]), ≥ 2 drugs acting on cytochrome P450 (OR = 2.24 [95% CI 2.07–2.46]), and ATC codes B (OR = 1.89 [95% CI 1.05–2.08]) and C (OR = 4.01 [95% CI 3.55–4.57]) were associated with potential DDIs. Conclusion. Special care should be taken with the prescription and therapeutic follow-up of patients who present characteristics identified as predictors. Knowledge of potential DDI predictors could aid in developing preventive practices and policies that allow public health services to better manage this situation.

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.
CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes
Authors: Dragoni Stefania , Materozzi Giada , Pessina Federica , Frosini Maria , Marco José Luis , Unzeta Mercedes , Sgaragli Giampietro , Valoti Massimo
Published: March 2016

Purpose. The selective monoamine oxidase-B (MAO-B) inhibitor, l-deprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and l-methamphetamine. Subsequently, this has promoted the design of a novel, more potent, MAO-B inhibitor PF9601N, which also has neuroprotective and antioxidant properties. The aim of this work was to investigate the effect of treatment with PF9601N on its own phase I hepatic metabolism. Kinetic parameters of PF9601N CYP-dependent N-dealkylation reaction was also studied and compared with those of l-deprenyl. Methods. C57BL/6 mice were treated with PF9601N for 4 days. After CYP content and related monooxygenase activities were assayed in liver microsomes of control and treated animals. Results. CYP activities, cytochrome b5 content, NADPH-cytochrome P450 reductase and various monooxygenase activities were unaffected by in vivo PF9601N treatment. With microsomes from both control and treated mice, the PF9601N-dealkylation product, FA72, was the only detected metabolite with its formation rate following an hyperbolic, Michaelis-Menten curve. Among various inhibitors, only ketoconazole inhibited the FA72 formation rate, indicating a major involvement for CYP3A. Apparent Km and Vmax values generated by human liver microsomes were similar to those found with mouse microsomes. Ketoconazole inhibition indicates that CYP3A is one of the major enzymes involved in PF9601N metabolism also by human liver microsomes. In mouse liver microsomes, the intrinsic clearance of PF9601N was significantly lower than that of l-deprenyl suggestive of an improved bioavailability for the former. Conclusion. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.
First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy
Authors: Ping Wang , Tao Yin , HongYing Ma , DanQi Liu , Yanghao Sheng , BoTing Zhou
Published: March 2016

Purpose: Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). Methods: Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). Results: In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. Conclusion: CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.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.
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.
Investigation of DNA Spectral Conformational Changes and Polymer Buffering Capacity in Relation to Transfection Efficiency of DNA/Polymer Complexes
Authors: Cherng Jong Yuh
Published: March 2016

Purpose. The relation between transfection efficiency of DNA/polymer complexes and DNA conformational alterations is investigated. The buffering capacity of several synthetic polymers is also studied to relate their performance in transfection efficiency. Methods. The cationic polymer/DNA interaction was evaluated by measuring the alteration of DNA secondary structures in solution before and after the addition of polymer with ATR-FTIR technique. The degree of protonation in aqueous cationic polymers is varied upon pH and different structures. A polymer capable of protonation acts like a proton sponge to react with H+ in titration with HCl. This characteristic was evaluated in relation to transfection efficiency because the capacity would help the release of endocytotic DNA from endosome/lysosome on its way to expression. Results. IR results show that the antisymmetric PO2- vibration of DNA (at 1224 cm-1) shifts toward lower frequencies in complexation with PEI or PLLys (these polymers are able to transfect DNA). By contrast, the antisymmetric PO2- vibration of DNA in presence of PDAMA or dextran (these polymers are poor in DNA transfection) shows a shifting to higher frequencies or no alteration was observed. Interestingly, the polymers with best performance in transfection efficiency are in this order: PEI>PDMAEMA>PLLys>PDAMA>dextran which is in the same order as their polymer buffering capacity. These facts indicate polymers possessing better buffering capacity could result in higher transfection efficiency. Also, we have demonstrated in this paper that the antisymmetric PO2- stretching vibration in IR spectra is sensitive while binding of cationic polymers to DNA. These findings are useful for the development of polymer-based gene delivery systems with better performance in vitro and in vivo
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.
Cytochrome P450 3A4 and 2D6-Mediated Metabolism of Leisure and Medicinal Teas
Authors: Tam Teresa W , Liu Rui , Saleem Ammar , Arnason John Thor , Krantis Anthony , Foster Brian C
Published: March 2016

PURPOSE: Thirty-five commercially available Camellia sinensis (black and green) and herbal leisure teas and an assortment of Traditional Chinese medicinal teas were randomly selected and examined for their potential to inhibit the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). The study was then extended to examine CYP2D6*1 and CYP2D6*10. METHODS: Microtiter fluorometric assays were utilized to examine the potential for the teas to inhibit CYP-mediated metabolism. Aqueous or alcoholic extracts of the dried tea plant material were examined. METHODS: Most of the black and green leisure teas generally inhibited CYP3A4 more than the Chinese medicinal teas. The medicinal Chinese teas were generally more inhibitory towards CYP3A4 compared to the CYP2D6 isozymes, and the aqueous extracts displayed more potency than the alcoholic extracts. CONCLUSIONS: Tea whether used for leisure or medicinal purposes has the potential to inhibit CYP3A4-mediated drug metabolism particularly black tea.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.
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.
Cell-Derived Microparticles: New Targets in the Therapeutic Management of Disease
Authors: Bebawy Mary , Roseblade Ariane , Luk Frederick , Rawling Tristan , Ung Alison , Grau Georges E. R.
Published: March 2016

Intercellular communication is essential to maintain vital physiological activities and to regulate the organism’s phenotype. There are a number of ways in which cells communicate with one another. This can occur via autocrine signaling, endocrine signaling or by the transfer of molecular mediators across gap junctions. More recently communication via microvesicular shedding has gained important recognition as a significant pathway by which cells can coordinate the spread and dominance of selective traits within a population. Through this communication apparatus, cells can now acquire and secure a survival advantage, particularly in the context of malignant disease. This review aims to highlight some of the functions and implications of microparticles in physiology of various disease states, and present a novel therapeutic strategy through the regulation of microparticle production.

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.
Simultaneous Determination of Levocetirizine and Pseudoephedrine in Dog Plasma by Liquid Chromatography-Mass Spectrometry in the Presence of Dextrocetirizine
Authors: Ryu Jae Kuk , Yoo Sun Dong
Published: March 2016

Purpose. This study describes the development of a rapid and sensitive LC-ESI-MS assay for simultaneous enantioselective determination of levocetirizine and pseudoephedrine in dog plasma in the presence of dextrocetirizine. Methods. Separations were achieved on an Ultron ES-OVM chiral column using the mobile phase consisting of 10 mM aqueous NH4OAc (pH 6.6) and acetonitrile (9:1 v/v). Results. The retention times of pseudoephedrine, dextrocetirizine, levocetirizine and diazepam (internal standard) were 5.2, 8.3, 9.6 and 11.6 min, respectively, and the total run time was less than 15 min. The assay was validated to demonstrate the linearity, accuracy and precision, recovery and stability. The calibration curves were linear over the concentration range from 1 – 200 ng/mL for levocetirizine and from 5 – 1000 ng/mL for pseudoephedrine. Conclusions. The developed assay was successfully applied to a pharmacokinetic study after oral administration of the racemic cetirizine (0.5 mg/kg, or 0.25 mg/kg as levocetirizine) and pseudoephedrine (12 mg/kg) in the dog.

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.
Carboxymethyl-Starch Excipients for Gastrointestinal Stable Oral Protein Formulations Containing Protease Inhibitors
Authors: De Koninck Patrick , Archambault Denis , Hamel Francine , Sarhan Fathey , Mateescu Mircea Alexandru
Published: March 2016

Purpose. The aim of this study was to develop a formulation for bioactive compounds using Carboxymethyl Starch (CMS) as excipient containing protease inhibitors. This formulation provided gastro protection and enhanced stability against pancreatic enzymes. Such stability is needed for formulation of oral vaccines with specific antigens. Methods. CMS was synthesized by treatment of starch with monochloroacetic acid in conditions leading to a substitution degree of about 1 meq/g and used as excipient for monolithic devices (300 mg tablets). Pefabloc SC and Aprotinin inhibitors were tested in dissolution media and in formulation to prevent the degradation of released bioactive materials. To evaluate the structural integrity and biological stability of plant proteins in the CMS formulation, albumin and lipase were added to the plant protein extract as protein and respectively as enzyme markers. The amounts of released and recovered proteins were evaluated by SDS-PAGE and densitometric analysis. Results. It was found that 1.6 % (w/w) of Pefabloc SC provides 98 % protection of the released plant proteins for formulations of 30 % alfalfa protein extract (APE) with CMS. In addition, when bovine serum albumin (BSA) added to the plant protein extract as a marker, 90 % protection of the released BSA was observed. Furthermore, a much higher lipase activity was found in the releasing media when the formulations contained Pefabloc SC. Conclusion. Formulations with CM-Starch excipients and containing protease inhibitors prevent protein degradation and protect lipase activity, showing a marked potential to use for orally administered bioactive peptides and therapeutic enzymes.
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