bluuebunny/crossref_metadata_2025 huggingface dataset:
When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets
Authors: Seng Yue Corinne , Benvenga Salvatore , Scarsi Claudia , Loprete Luca , Ducharme Murray
Published: March 2016

Purpose:  Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. Methods: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 mg) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done. Results: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 18% vs. 14% for AUC0-6, 17% vs. 5% for AUC0-12 and 10% vs. 8% for AUC0-t). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in Tmax were found. Conclusions: Although both formulations are considered “bioequivalent” in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity. 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.
Extracellular Vesicles as Natural Nanosized Delivery Systems for Small-Molecule Drugs and Genetic Material: Steps towards the Future Nanomedicines
Authors: Kotmakçı Mustafa , Bozok Çetintaş Vildan
Published: March 2016

A new platform for drug, gene and peptide-protein delivery is emerging, under the common name of “extracellular vesicles”. Extracellular vesicles (EVs) are 30-1000 nm-sized cell-derived, liposome-like vesicles. Current research on EVs as nano-delivery systems for small-molecule drugs and genetic material, reveal that these tiny, biologically-derived vesicles carry a great potential to boost the efficacy of many therapeutic protocols. Several features of EVs; from efficacy to safety, from passive to active targeting ability, the opportunity to be biologically or chemically labelled, and most importantly, their eobiotic origin make them promising candidate for development of the next generation personalized nanomedicines. The aim of this article is to provide a view on the current research in which EVs are used as drug/genetic material delivery systems. Their application areas, drug loading and targeting strategies, and biodistribution properties are discussed.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.
Unconventional Treatment Options in Severe Asthma: An Overivew
Authors: Banh Hoan Linh
Published: March 2016

In Canada, asthma is the leading cause of admission in hospital. About of 80% of the death from asthma is preventable. Severe asthma is defined as a patient with persistent symptoms despite the use of adequate controller therapy, including multiple courses of oral glucocorticosteroids. However, about 10% of patients with severe asthma remain poorly controlled despite optimal treatment and these patients have the greatest morbidity and mortality. The management of refractory severe asthma remains extremely challenging.

For patients with refractory severe asthma, the adjunct therapies recommended by national guidelines only included oral glucocorticosteroid and anti-IgE antibody (omalizumab) therapy. Currently, there is limited published literature on the unconventional treatments of refractory severe asthma. The objective of this review article is to provide an updated therapeutic overview of unconventional treatment options for refractory severe asthma.

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.
Low-Surfactant Microemulsions for Enhanced Topical Delivery of Poorly Soluble Drugs
Authors: Shalviri Alireza , Sharma Avinash C , Patel Dipak , Sayani Amyn
Published: March 2016

Purpose: To develop and characterize low-surfactant microemulsion (ME) gels to enhance topical delivery of poorly soluble drugs. Method: Five low surfactant ME formulations were manufactured following the construction of pseudo-ternary phase diagrams. The MEs were screened for their ability to dissolve a poorly soluble new chemical entity (Model Drug X). Various viscosity imparting agents like Carbopol 934, Colloidal Silica, HPMC K100M, Lubrajel NP, and Xanthan Gum were evaluated for the manufacture of these ME gels. Each ME gel was then further evaluated for physical stability, including assessing rheological profiles. In vitro release profiles were also determined and compared to a conventional ointment. Results: Three of the five low surfactant MEs developed (ME1, ME4 and ME5) were capable of dissolving Model Drug X up to 14 fold higher than the conventional ointment formulation. ME1 and ME4 gels comprising Xanthan gum or Carbopol 934 were physically stable, while ME5 gel was stable only with Colloidal Silica. The ME5 gel with Colloidal Silica showed an irreversible increase in its elastic modulus when exposed to high temperature, indicating that the formulation would be less suitable for commercial use. The Xanthan Gum and Colloidal Silica gels yielded significantly higher release rates (8 - 10 fold) compared to a conventional ointment and formulations containing Carbopol 934. The significant difference in drug release rates between Xanthan Gum and Carbopol 934 indicated that choice of viscosity imparting agent played an important role in governing drug release from ME gels. Conclusion: ME gels were developed with low surfactant concentrations and improved formulation characteristics, which increased the solubility and subsequent release of a poorly soluble drug.

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.
Crushed Tablets: Does the Administration of Food Vehicles and Thickened Fluids to Aid Medication Swallowing Alter Drug Release?
Authors: Manrique-Torres Yady Juliana , Lee Danielle J , Islam Faiza , Nissen Lisa M , Cichero Julie A.Y. , Stokes Jason R , Steadman Kathryn J
Published: March 2016

Purpose. To evaluate the influence of co-administered vehicles on in vitro dissolution in simulated gastric fluid of crushed immediate release tablets as an indicator for potential drug bioavailability compromise. Methods. Release and dissolution of crushed amlodipine, atenolol, carbamazepine and warfarin tablets were tested with six foods and drinks that are frequently used in the clinical setting as mixers for crushed medications (water, orange juice, honey, yoghurt, strawberry jam and water thickened with Easythick powder) in comparison to whole tablets. Five commercial thickening agents (Easythick Advanced, Janbak F, Karicare, Nutilis, Viscaid) at three thickness levels were tested for their effect on the dissolution of crushed atenolol tablets. Results. Atenolol dissolution was unaffected by mixing crushed tablets with thin fluids or food mixers in comparison to whole tablets or crushed tablets in water, but amlodipine was delayed by mixing with jam. Mixing crushed warfarin and carbamazepine tablets with honey, jam or yoghurt caused them to resemble the slow dissolution of whole tablets rather than the faster dissolution of crushed tablets in water or orange juice. Crushing and mixing any of the four medications with thickened water caused a significant delay in dissolution. When tested with atenolol, all types of thickening agents at the greatest thickness significantly restricted dissolution, and products that are primarily based on xanthan gum also delayed dissolution at the intermediate thickness level. Conclusions. Dissolution testing, while simplistic, is a widely used and accepted method for comparing drug release from different formulations as an indicator for in vivo bioavailability. Thickened fluids have the potential to retard drug dissolution when used at the thickest levels. These findings highlight potential clinical implications of the addition of these agents to medications for the purpose of dose delivery and indicate that further investigation of thickened fluids and their potential to influence therapeutic outcomes is warranted. 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.
Hepatotoxicity of Pyrrolizidine Alkaloids
Authors: Neuman Manuela G , Cohen Lawrence , Opris Mihai , Nanau Radu M , Jeong Hyunjin
Published: March 2016

PURPOSE: This article aimed 1) to review herbal medicine containing pyrrolizidine alkaloids (PA)-induced toxicities of the liver; 2) to encourage the recognition and prevention of common problems encountered when using complementary and alternative medicine and 3) to review the toxic effects of herbal remedies containing PAs. DESIGN AND METHODS: We performed a systematic literature search using the PubMed and Google Scholar engines. The search was not restricted to languages. We also provide an interpretation of the data. CONCLUSIONS: Herbal remedies containing PAs can induce liver damage, including hepato- sinusoidal obstruction syndrome or veno-occlusive disease. Preventing overdose and monitoring long-term use of such remedies may avoid glutathione depletion leading to mitochondrial injury, and therefore avoid liver cell damage. Moreover, immediately stopping the herbal medication prevents further harm to the liver. Chronic consumption of hepatotoxicants can lead to cancer formation and promotion. The role of active metabolites in PA-induced liver toxicity and their mechanism of action require further investigation. 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.
Liposomal Drug Delivery: A Versatile Platform for Challenging Clinical Applications
Authors: Madni Asadullah , Sarfraz Muhammad , Rehman Mubashar , Ahmad Mahmood , Akhtar Naveed , Ahmad Saeed , Tahir Nayab , Ijaz Shakeel , Al-Kassas Raida , Löbenberg Raimar
Published: March 2016

Liposomes are lipid based vesicular systems that offer novel platform for versatile drug delivery to target cell. Liposomes were first reported by Bangham and his co-workers in 1964 (1). Since then, liposomes have undergone extensive research with the prime aim to optimize encapsulation, stability, circulation time and target specific drug delivery. Manipulation of a liposome’s lipid bilayer and surface decoration with selective ligands has transformed conventional liposomes into adaptable and multifunctional liposomes. Development of liposomes with target specificity provide the prospect of safe and effective therapy for challenging clinical applications. Bioresponsive liposomes offer the opportunity to release payload in response to tissue specific microenvironment. Incorporation of novel natural and synthetic materials has extended their application from stable formulations to controlled release targeted drug delivery systems. Integration and optimization of multiple features into one system revolutionized research in the field of cancer, gene therapy, immunotherapy and infectious diseases. After 50 years since the first publication, this review is aimed to highlight next generation of liposomes, their preparation methods and progress in clinical applications. 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.
Alkylphospholipids – A Promising Class of Chemotherapeutic Agents with a Broad Pharmacological Spectrum
Authors: Almeida Pachioni Juliana De , Magalhães Juliana Gallottini , Cardoso Lima Elys Juliane , Moura Bueno Luciana De , Barbosa Joyce Ferreira , Malta de Sá Matheus , Rangel-Yagui Carlota Oliveira
Published: March 2016

PURPOSE: Since when alkylphospholipds (ALPs) were discovered and, even further after miltefosine’s approval for the treatment of cutaneous metastasis of breast cancer and leishmaniasis, their activity against many other diseases have been extensively studied. This review aims to provide a summary of the alkylphospholipids’ applications investigated so far. RESULTS: The mechanism of action of ALPs is not fully understood, however it is believed that they interfere with lipid homeostasis leading to cell apoptosis. Due to ALPs cytotoxic activity, this class of molecules has shown to be effective against many diseases and conditions. Besides the approval of miltefosine for application in cutaneous metastasis of breast cancer and visceral and cutaneous leishmaniasis, several other analogs have proved efficacy and are promising as less toxic alternatives. ALPs have also shown in vitro and in vivo activity against Trypanosoma spp., amoebae, Tricomonas vaginalis, Schistosoma mansoni, HIV, and some fungi and bacteria species. The use of ALPs for intraocular lens coating is also under investigation. In addition, a clinical trial comparing miltefosine with usual treatments to spontaneous urticaria is also being conducted. CONCLUSIONS: Alkylphospholipids present such a broad pharmacological spectrum that justifies the need for further investigations of the drug class mechanisms of action, as well as the search for new analogs with improved activity and toxicological profiles.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.
Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir
Authors: Cusato Jessica , Allegra Sarah , De Nicolò Amedeo , Boglione Lucio , Fatiguso Giovanna , Mohamed Abdi Adnan , Cariti Giuseppe , Di Perri Giovanni , D’Avolio Antonio
Published: March 2016

PURPOSE: Triple therapy for HCV-1 infection consists in boceprevir or telaprevir, ribavirin and PEG-interferon. Telaprevir is a P-glycoprotein substrate and it is metabolized by CYP3A4/5. No data have been published on intracellular penetration of telaprevir. We determined peripheral blood mononuclear cells (PBMCs) and trough plasma S and R telaprevir isomers concentrations; moreover, we evaluated the influence of some single nucleotide polymorphisms (SNPs) on these pharmacokinetic data after 1 month of triple therapy in humans. METHODS: Plasma and intracellular telaprevir concentrations were determined at the end of dosing interval (Ctrough) using ULPC-MS/MS validated methods; allelic discrimination was performed through real-time PCR. RESULTS: Median telaprevir Ctrough plasma concentrations were 2579 ng/mL and 2233 ng/mL for the pharmacologically more active S, and R, enantiomers, respectively, with median S/R plasma ratio of 1.11. In PBMC, the medians were 6863 ng/mL and 1096 ng/mL for S and R, respectively, with median S/R being 5.73. The PBMC:plasma ratio for S was 2.59 for R. Plasma ribavirin concentrations were directly correlated with plasma S-telaprevir concentrations. In linear regression analysis, only CYP24A1_rs2585428 SNP (p=0.003) and body mass index (p=0.038) were able to predict S-telaprevir PBMC concentrations. CONCLUSIONS: Our preliminary data could increase the understanding of mechanisms underlying telaprevir intracellular and plasma exposure, suggesting the implementation of pharmacogenetics in these drug kinetic studies. 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.
Progressive Steps of Polymorphic Transformation of Gabapentin Polymorphs Studied by Hot-stage FTIR Microspectroscopy
Authors: Hsu Cheng-Hung , Ke Wen-Ting , Lin Shan-Yang
Published: March 2016

Purpose. The aim of this study was to determine the progressive processes of polymorphic transformation of different gabapentin (GBP) polymorphs by using hot-stage Fourier transform infrared (FTIR) microspectroscopy. Methods. Four polymorphs of GBP were previously prepared and then identified by differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, FTIR microspectroscopy and X-ray powder diffractometry. A novel hot-stage FTIR microspectroscopic technique was used to investigate the progressive steps of polymorphic transformation of each GBP polymorph sealed within two pieces of KBr plates. Results. Four polymorphs (Forms I, II, III and IV) of GBP were well characterized. The GBP form I was proven to be a monohydrate, but other GBP forms II-IV were anhydrous. Different thermal-induced progressive processes and steps of polymorphic interconversion of GBP polymorphs were clearly found from the changes in the three-dimensional IR spectral contour and peak intensity by using hot-stage FTIR microspectroscopy. The results also indicate that GBP form I was dehydrated and transformed to form III, and then converted to form IV; whereas GBP forms II and III directly transformed to form IV during heating. The GBP form IV was the last polymorph before the intramolecular lactamization of GBP. Conclusion. A one-step novel hot-stage FTIR microspectroscopy was successfully applied to simultaneously and continuously investigate the progressive processes and steps of thermal-induced polymorphic interconversion of GBP polymorph in the solid state.
Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products
Authors: Borg John Joseph , Robert Jean-Louis , Wade George , Aislaitner George , Pirozynski Michal , Abadie Eric , Salmonson Tomas , Bonanno Patricia Vella
Published: March 2016

ABSTRACT – Purpose. The aim of this study was to identify common trends in the deficiencies identified in the quality part of the dossier during the evaluation of marketing authorisation applications for medicinal products for human use submitted through the EU’s centralised procedure. Methods. We analysed all the adopted Day 120 list of questions on the quality module of 52 marketing authorisation applications for chemical entity medicinal products submitted to the European Medicines Agency and evaluated by the Committee for Medicinal Products for Human Use (CHMP), during 12 consecutive plenary meetings held in 2007 and 2008. Subsequently we calculated the frequency of common deficiencies identified across these applications. Results. Frequencies and trends on quality deficiencies have been recorded and presented for 52 marketing authorisation applications. 32 “Major Objections” originated from 13 marketing authorisation applications. 13 concerned were raised regarding drug substances and 19 for drug products. Furthermore, 905 concerns on drug substance and 1,054 on drug product were also adopted. Conclusions. The impact of the frequencies and trends in quality deficiencies that were identified are discussed from a regulatory point of view. It is expected that the results of this study will not only be of interest to pharmaceutical companies but will also aid regulators’ in obtaining consistent information on drug products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.
Emergence of power laws in the pharmacokinetics of paclitaxel due to competing saturable processes.
Authors: Tuszynski Jack A , Marsh Rebeccah E. , Sawyer Michael B. , Vos Kenneth J.E.
Published: March 2016

Purpose: This study presents the results of power law analysis applied to the pharmacokinetics of paclitaxel. Emphasis is placed on the role that the power exponent can play in the investigation and quantification of nonlinear pharmacokinetics and the elucidation of the underlying physiological processes. Methods: Forty-one sets of concentration-time data were inferred from 20 published clinical trial studies, and 8 sets of area under the curve (AUC) and maximum concentration (Cmax) values as a function of dose were collected. Both types of data were tested for a power law relationship using least squares regression analysis. Results: Thirty-nine of the concentration-time curves were found to exhibit power law tails, and two dominant fractal exponents emerged. Short infusion times led to tails with a single power exponent of -1.57 ± 0.14, while long infusion times resulted in steeper tails characterized by roughly twice the exponent. The curves following intermediate infusion times were characterized by two consecutive power laws; an initial short slope with the larger alpha value was followed by a crossover to a long-time tail characterized by the smaller exponent. The AUC and Cmax parameters exhibited a power law dependence on the dose, with fractional power exponents that agreed with each other and with the exponent characterizing the shallow decline. Computer simulations revealed that a two- or three-compartment model with both saturable distribution and saturable elimination can produce the observed behaviour. Furthermore, there is preliminary evidence that the nonlinear dose-dependence is correlated with the power law tails. Conclusion: Assessment of data from published clinical trials suggests that power laws accurately describe the concentration-time curves and non-linear dose-dependence of paclitaxel, and the power exponents provide insight into the underlying drug mechanisms. The interplay between two saturable processes can produce a wide range of behaviour, including concentration-time curves with exponential, power law, and dual power law tails.
Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function
Authors: Llaudó Inés , Cassis Linda , Torras Joan , Bestard Oriol , Franquesa Marcel·la , Cruzado Josep M. , Cerezo Gema , Castaño Esther , Petriz Jordi , Herrero-Fresneda Immaculada , Grinyó Josep M. , Lloberas Núria
Published: March 2016

Purpose. P-glycoprotein (Pgp) is a member of the ABC-transporter family that transports substances across cellular membranes acting as an efflux pump extruding drugs out of the cells. Pgp plays a key role on the pharmacokinetics of several drugs. Herein, we have studied the effects of immunosuppressants on Pgp function, assessing rhodamine-123 (Rho123) uptake and efflux in different T-cell subsets. Methods. Different immunosuppressants such as Cyclosporine (CsA), Rapamycin (Rapa) and Tacrolimus (Tac) were used to assess the in vitro effect on Pgp function of main T-cell subsets among healthy volunteers. We measured Rho123 uptake, efflux and kinetic of extrusion in CD4+ and CD8+ subsets by flow cytometry. Antigen-specific memory T-cell responses were assessed by measuring T-cell proliferation and cytokine secretion using an allogeneic mixed lymphocyte reaction. Results. Rho123 uptake in groups treated with CsA and CsA+Rapa was significantly decreased compared to non-treated group and the other immunosupressants in both T cells subsets. Pgp activity was also reduced in CsA and CsA+Rapa compared to the other immunosupressants but it was only significant in the CsA group for CD8+ subset. Kinetic extrusion of Rho123 by Pgp in all groups was faster in CD8+ T cells. All immunosuppressants and the specific Pgp inhibitor PSC833 diminished antigen-primed T-cell proliferation, especially CD8+ T-cell subset. Conclusions. Our data indicate that small molecules immunosuppressants, especially CsA, inhibit Pgp activity and T-cell function being the CD8+ T cells more susceptible to this effect. These findings support the importance of Pgp when designing combined immunosuppressive regimens.

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.
Chondroitin Sulfate Capsule System for Efficient and Secure Gene Delivery
Authors: Kurosaki Tomoaki , Kitahara Takashi , Fumoto Shintaro , Nishida Koyo , Yamamoto Kayo , Nakagawa Hiroo , Kodama Yukinobu , Higuchi Norihide , Nakamura Tadahiro , Sasaki Hitoshi
Published: March 2016

Purpose. In this study, we developed various ternary complexes of encapsulated polyplexes and lipoplexes using chondroitin sulfate (CS) and investigated their universal usefulness for gene delivery. Methods. To prepare the cationic complexes, pDNA was mixed with some cationic vectors such as poly-L-arginine, poly-L-lysine, N-[1-(2, 3-dioleyloxy) propyl]-N, N, N-trimethylammonium chloride (DOTMA)-cholesterol liposomes, and DOTMA- dioleylphosphatidylethanolamine (DOPE) liposomes. CS was added to the cationic complexes for constructions of ternary complexes. We examined in vitro transfection efficiency, cytotoxicity, hematotoxicity, and in vivo transfection efficiency of the ternary complexes. Result. The cationic polymers and cationic liposomes bound to pDNA and formed stable cationic polyplexes and lipoplexes, respectively. Those cationic complexes showed high transgene efficiency in B16-F10 cells; however, they also had high cytotoxicity and strong agglutination with erythrocytes. CS could encapsulate the polyplexes and lipoplexes and form stable anionic particles without disrupting their structures. The ternary complexes encapsulated by CS showed high transgene efficiency in B16-F10 cells with low cytotoxicity and agglutination. As the result of animal experiments, the polyplexes had little transgene efficiency after intravenous administration in mice, whereas polyplexes encapsulated by CS showed specifically high transgene efficiency in the spleen. The capsulation of CS, however, reduced the high transgene efficiency of the lipoplexes. Conclusion. These results indicate that CS can contribute to polyplex-mediated gene delivery systems for effective and safe gene therapy.
Discovery of Chlorogenic Acid-Based Peptidomimetics as a Novel Class of Antifungals. A Success Story in Rational Drug Design
Authors: Daneshtalab Mohsen
Published: March 2016

Life-threatening fungal infections have increased dramatically in recent decades in immunocompromised patients. An estimated 40% of all deaths from hospital-acquired infections are due to infections caused by opportunistic fungi. The current treatment options are either causing serious toxicity, or becoming inactive against the drug-resistant fungal strains. Thus, the discovery and development of new antifungal agents that are economically feasible, have excellent therapeutic value, and address the problems of toxicity and species resistance is very important. We have recently designed and synthesized a series of chlorogenic acid-based peptidimimetics using structure-based methodology starting with cyclic peptides of the candin class of antifungals. These novel and totally synthetic compounds exhibit promising antifungal activity against pathogenic fungi with very low toxicity against brine shrimps. The possible novelty in their mechanism of action and economically feasible synthetic approach are the attractive features of this class of compounds that make them different from the already utilized antifungal agents.
The New Face of Hyperlipidemia Management: Proprotein Convertase Subtilisin/Kexin Inhibitors (PCSK-9) and Their Emergent Role As An Alternative To Statin Therapy
Authors: Smith Lillian , Mosley Juan , Yates Jarah , Caswell Luke
Published: March 2016

This review analyzes Proprotein Convertase Subtilisin/Kexin 9 inhibitors (PCSK-9), a new medication class that has arisen in the last year to combat hypercholesterolemia. They are targeted towards patients who are unable to achieve acceptable low density lipoprotein (LDL) levels despite maximum statin therapy, as well as those who are unable to tolerate maximum statin therapy due to side effects such as myopathy or myalgia. Two of these medications have been released in the last year: alirocumab (Praluent) and evolocumab (Repatha). This article will overview this medication class, describe their pathophysiology, and analyze the clinical data from the numerous studies and trials done on both of these medications for their efficacy and safety outcomes. Data compiled on this new class of medications support the research that PCSK-9 inhibitors are both a safe and effective means of lowering the LDL levels of resistant or otherwise currently unmanaged hypercholesterolemia patients.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.
Reciprocal Powered Time model for Release Kinetic Analysis of Ibuprofen Solid Dispersions in Oleaster Powder, Microcrystalline Cellulose and Crospovidone
Authors: Mohammadi Ghobad , Barzegar-Jalali Mohammad , Valizadeh Hadi , Nazemiyeh Hossein , Barzegar-Jalali Azim , Siahi Shadbad Mohammad Reza , Adibkia Khosro , Zare Masoud
Published: March 2016

ABSTRACT- Purpose. A physically sound derivation for reciprocal power time (RPT) model for kinetic of drug release is given. In order to enhance ibuprofen dissolution, its solid dispersions (SDs) prepared by cogrinding technique using crospovidone (CP), microcrystalline cellulose (MC) and oleaster powder (OP) as a novel carrier and the model applied to the drug release data. Methods. The drug cogrounds with the carriers were prepared and subjected to the dissolution studies. For elucidation of observed in vitro differences, FT-IR spectroscopy, X-ray diffraction patterns, DSC thermograms and laser particle size measurement were conducted. Results. All drug release data fitted very well to newly derived RPT model. The efficiency of the carriers for dissolution enhancement was in the order of: CP>OP>MC. The corresponding release kinetic parameter derived from the model, t50% (time required for 50% dissolution) for the carrier to drug ratio 2:1 were 2.7, 10.2 and 12.6 min, respectively. The efficiency of novel carrier, OP, was between CP and MC. FT-IR showed no interaction between the carriers and drug. The DSC thermograms and X-ray diffraction patterns revealed a slight reduced crystallinty in the SDs. Also grinding reduced mean particle size of drug from 150.7 to 44.4 µm. Conclusion. An improved derivation for RPT model was provided which the parameter of the model, t50%, unlike to previous derivations was related to the most important property of the drug i.e. its solubility. The model described very well drug release kinetics from the solid dispersions. Cogrinding was an effective technique in enhancing dissolution rate of ibuprofen. Elaeagnus angostifolia fruit powder was suggested as a novel potential hydrophilic carrier in preparing solid dispersion of ibuprofen.
Oral immunization against hepatitis B using bile salt stabilized vesicles (bilosomes)
Authors: Shukla Anshuman , Khatri Kapil , Gupta Prem N , Goyal Amit K , Mehta Abhinav , Vyas Suresh P
Published: March 2016

PURPOSE: Presently available hepatitis B vaccine is administered through parenteral route and fails to induce mucosal antibody response. Oral immunization appears to be an effective and attractive alternative to the parenteral immunization. However, the problem of degradation of antigen in harsh and hostile environment of the gastrointestinal tract consequently requires larger dose and more frequent dosing of antigen. Furthermore, much larger dose can induce systemic tolerance. In order to overcome these problems bile salt stabilized vesicles (bilosomes) can be used, which could provide both protection to antigen as well as transmucosal uptake and subsequent resultant systemic immunity. Another purpose of this study was to determine the dose that could produce comparable serum antibody titre against hepatitis B through oral route as obtained after intramuscular immunization. METHODS: In the present study bilosomes containing recombinant hepatitis B surface antigen were prepared by cast film method. HBsAg loaded bilosomes were characterized in vitro for their shape, size, percent entrapment and stability. The fluorescence microscopy was carried out to confirm the uptake of bilosomes by gut associated lymphoid tissues (GALT). The in vivo study was comprised of estimation of anti-HBsAg IgG response in serum and anti-HBsAg sIgA in various body secretions using specific ELISA techniques following oral immunization with low dose loaded bilosomes (BSSV1, 10 µg), intermediate dose loaded bilosomes (BSSV2, 20 µg) and high dose loaded bilosomes (BSSV3, 50 µg) in Balb/c mice. RESULTS: The fluorescence microscopy suggests that an increase in fluorescence intensity following the uptake of bilosomes entrapped FITC-BSA in gut associated lymphoid tissues. The high dose HBsAg bilosomes (BSSV3, 50 µg) produced comparable anti-HBsAg IgG levels in serum to those observed in the case of intramuscular administration of alum adsorbed HBsAg (10 µg). However, alum adsorbed HBsAg was unable to produce sIgA in mucosal secretions, whilst, all bilosomal preparations could elicit measurable sIgA in mucosal secretions, where the highest responses were observed in high dose HBsAg bilosomes (BSSV3, 50µg). CONCLUSIONS: HBsAg loaded bilosomes produced both systemic as well as mucosal antibody responses upon oral administration. Thus bilosomes may emerge out to be potential carriers for non invasive mucosal immunization.
Dry Powder Coating using Planetary Centrifugal Mixer
Authors: Miyazaki Yasunori , Miyawaki Kaoru , Uchino Tomonobu , Kagawa Yoshiyuki
Published: March 2016

Purpose: Extemporaneous compounding is an important part of pharmacy practice, and should be standardized and sophisticated to ensure the quality of the compounded preparations. Recently, we applied a planetary centrifugal mixer (PCM) to powder blending, which has attracted interest for its small scale and lack of contamination. In this study, we aimed to reveal the feasibility of dry powder coating through ordered mixing of fine particles using PCM. Methods: Cohesive lactose powders (Pharmatose450M) were dry coated with magnesium stearate (MgSt) using from 0.1 to 5%(w/w) content. The operational variables tested were operation time (1-30 min), operation speed (400-1000 rpm), vessel size (24-100 mL), and charging rate in the vessel (20-40%). The processed powders were evaluated for their surface morphology, flowability, and wettability. Furthermore, fine ibuprofen particles were coated with various lubricants, and then the dissolution profiles were examined. The crystallinity of ibuprofen was assessed using FT-IR and PXRD. Results: Lactose powders were successfully coated with MgSt using PCM. When the level of MgSt was over 1%, the surface of the lactose powders was thoroughly covered. Angles of repose were 51° and 41° for unprocessed and processed powders with 1% MgSt, respectively. The contact angle of the water drop on the 1% MgSt sample leached to be 132°, changing to a hydrophobic surface. Investigations under various operational conditions revealed that higher improvement was observed upon higher speed and longer time, and a smaller charging rate in the vessel. Vessel size had no impact. Moreover, improved dissolution of ibuprofen coated with both hydrophilic and hydrophobic lubricants was observed owing to good dispersing behavior. Besides, no alteration of crystallinity was detected. Conclusions: PCM is an effective tool for dry powder coating with low impact stress. The presented method will contribute a great deal to making crushed tablets a functional powder. 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.
Sub-Maximal Exercise Altered the Prednisolone Absorption Pattern.
Authors: Chien Kuei-Yu , Chen Ting-Ting , Hsu Jia , Pan Ryh-Nan , Li Jih-Heng , Kuo Chia-Hua , Hsu Mei-Chich
Published: March 2016

PURPOSE: Prednisolone has been widely used due to its relatively short pituitary inhibition and its moderate potency. Exercise is one of the non-pharmacological interventions for glucocorticoid- induced osteoporosis prevention. However, the effects of exercise on the pharmacokinetics of prednisolone were unclear. The purpose of this study was to evaluate the effects of sub-maximal exercise on the pharmacokinetics of prednisolone. METHODS: A randomized, double-blind, cross-over experimental design was used. Subjects needed to undertake two trials: a non-exercise trial (NE) and an exercise trial (E). After the first blood sampling, the subjects consumed 5mg of prednisolone with 100mL of water and then took a rest for 30 min. In the E trial, subjects cycled at 70% VO2max intensity until exhaustion. When subjects underwent the NE trial, they remained seated for the duration of the experiment. Serial blood samples were collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12h after prednisolone administration. Prednisolone and cortisol concentration were analyzed with a validated high performance liquid chromatographic method. RESULTS: This study indicated that the maximum concentration of the E trial was significantly lower than the NE trial (p
Pharmacokinetics and Pharmacodynamics of diclofenac in the presence and absence of glibenclamide in the rat
Authors: León-Reyes María R , Castañeda-Hernández Gilberto , Ortiz Mario I
Published: March 2016

PURPOSE. There are evidences that glibenclamide, a sulfonylurea antidiabetic agent, reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. The purpose of this work was to examine in the rat if such interaction involves pharmacokinetic mechanisms or is solely limited to the pharmacodynamic level. METHODS. All studies were carried out in female Wistar rats. Analgesia was assessed using the formalin test. Fifty microliters of diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection and a reduction in formalin-induced flinching was interpreted as an analgesic response. Rats were treated with oral diclofenac (3-18 mg/kg) in presence and the absence of oral glibenclamide (1-30 mg/kg). To evaluate the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (18 mg/kg) was studied in presence and the absence of glibenclamide (10 mg/kg). RESULTS. Oral administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Coadministration of glibenclamide significantly reduced diclofenac-induced antinociception. Notwithstanding, the interaction does no appear to involve pharmacokinetic mechanisms, as oral glibenclamide failed to produce any significant alteration in oral diclofenac bioavailability. CONCLUSION. Concomitant systemic administration of glibenclamide and diclofenac results in a reduction of the analgesic effect of the NSAID in the formalin test in the rat. This interaction, however, appears due solely to a pharmacodynamic mechanisms as diclofenac pharmacokinetics are not altered.
Application of 12S rRNA Barcodes for the Identification of Animal-Derived Drugs
Authors: Luo Jiaoyang , Yan Dan , Zhang Da , Han Yumei , Dong Xiaoping , Yang Yong , Deng Kejun , Xiao Xiaohe
Published: March 2016

Purpose. Animal-derived drugs are the major source of biological products and traditional medicine, but they are often difficult to identify, causing confusion in the clinical application. Among these medicinal animals, a number of animal species are endangered, leading to the destruction of biodiversity. The identification of animal-derived drugs and their alternatives would be a first step toward biodiversity conservation and safe medication. Until now, no effective method for identifying animal-derived drugs has been demonstrated; DNA-based species identification presents a brand-new technique. Methods. We designed primers to amplify a 523-bp fragment of 12S rRNA and generated sequences for 13 individuals within six medicinal animal species. We examined the efficiency of species recognition based on this sequence, and we also tested the taxonomic affiliations against the GenBank database. Results. All the tested drugs were identified successfully, and a visible gap was found between the inter-specific and intra-specific variation. We further demonstrated the importance of data exploration in DNA-based species identification practice by examining the sequence characteristics of relative genera in GenBank. This region of the 12S rRNA gene had a 100% success rate of species recognition within the six medicinal animal species. Conclusions. We propose that the 12S rRNA locus might be universal for identifying animal-derived drugs and their adulterants. The development of 12S rRNA for indentifying animal-derived drugs that share a common gene target would contribute significantly to the clinical application of animal-derived drugs and the conservation of medicinal animal species.

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Targeting the C-type Lectins-Mediated Host-Pathogen Interactions with Dextran
Authors: Pustylnikov Sergey , Sagar Divya , Jain Pooja , Khan Zafar K
Published: March 2016

Dextran, the α-1,6-linked glucose polymer widely used in biology and medicine, promises new applications. Linear dextran applied as a blood plasma substitute demonstrates a high rate of biocompatibility. Dextran is present in foods, drugs, and vaccines and in most cases is applied as a biologically inert substance. In this review we analyze dextran's cellular uptake principles, receptor specificity and, therefore, its ability to interfere with pathogen–lectin interactions: a promising basis for new antimicrobial strategies. Dextran-binding receptors in humans include the DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3-grabbing nonintegrin) family receptors: DC-SIGN (CD209) and L-SIGN (the liver and lymphatic endothelium homologue of DC-SIGN), the mannose receptor (CD206), and langerin. These receptors take part in the uptake of pathogens by dendritic cells and macrophages and may also participate in the modulation of immune responses, mostly shown to be beneficial for pathogens per se rather than host(s). It is logical to predict that owing to receptor-specific interactions, dextran or its derivatives can interfere with these immune responses and improve infection outcome. Recent data support this hypothesis. We consider dextran a promising molecule for the development of lectin–glycan interaction-blocking molecules (such as DC-SIGN inhibitors) that could be applied in the treatment of diseases including tuberculosis, influenza, hepatitis B and C, human immunodeficiency virus infection and AIDS, etc. Dextran derivatives indeed change the pathology of infections dependent on DC-SIGN and mannose receptors. Complete knowledge of specific dextran–lectin interactions may also be important for development of future dextran applications in biological research and medicine. 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.
A Correlative Model to Predict In Vivo AUC for Nanosystem Drug Delivery with Release Rate-Limited Absorption
Authors: Barzegar-Jalali Mohammad , Mohammadi Kaivan , Mohammadi Ghobad , Valizadeh Hadi , Barzegar-Jalali Azim , Adibkia Khosro , Nokhodchi Ali
Published: March 2016

Purpose. Drug release from nanosystems at the sites of either absorption or effect biophase is a major determinant of its biological action. Thus, in vitro drug release is of paramount importance in gaining insight for the systems performance in vivo. Methods. A novel in vitro in vivo correlation, IVIVC, model denoted as double reciprocal area method was presented and applied to 19 drugs from 55 nano formulations with total 336 data, gathered from literature. Results. The proposed model correlated the in vitro with in vivo parameters with overall error of 12.4 ± 3.9%. Also the trained version of the model predicted the test formulations with overall error of 15.8 ± 3.7% indicating the suitability of the approach. A theoretical justification was provided for the model considering the unified classical release laws. Conclusion. The model does not necessitate bolus intravenous drug data and seems to be suitable for IVIVC of drugs with release rate-limited absorption.

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Comparison of Pain Tolerance between Opioid Dependent Patients on Methadone Maintenance Therapy (MMT) and Opioid Naive Individuals
Authors: Zahari Zalina , Lee Chee Siong , Ibrahim Muslih Abdulkarim , Musa Nurfadhlina , Mohd Yasin Mohd Azhar , Lee Yeong Yeh , Tan Soo Choon , Mohamad Nasir , Ismail Rusli
Published: March 2016

Purpose: This study compared pain sensitivity among opioid dependent patients on methadone maintenance therapy (MMT) and opioid naive subjects. Methods: The three hundred participants comprised 152 opioid naive subjects and 148 opioid dependent patients. Opioid naive subjects had not taken any opioids including morphine and methadone to their best knowledge and were presumed so after two consecutive negative urine screenings for drugs. All opioid dependent patients were stabilized in treatment, defined as having been enrolled in the program for more than one month with no change of methadone dosage over the past one month. Excluded from the study were individuals with chronic or ongoing acute pain and individuals with a history of analgesics ingestion within 3 d before the cold pressor test (CPT). Pain tolerance to CPT was evaluated at 0 h, and at 2, 4, 8, 12, and 24 h post-methadone dose. Results: Patients exhibited a significantly shorter mean pain tolerance time of 34.17 s (95% CI 24.86, 43.49) versus 61.36 (52.23, 70.48) [p < 0.001] compared with opioid naive subjects. Time-dependent mean pain tolerance was also significantly different when naive subjects were compared to patients (p = 0.016). Conclusions: This study revealed hyperalgesia amongst patients on MMT, as manifested by their quicker hand withdrawal. The complaints of pain in this population should not be underestimated and the pain should be evaluated seriously and managed aggressively. 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.