Publications by authors named "Sai H S Boddu"

48 Publications

Resveratrol-loaded nanomedicines for cancer applications.

Cancer Rep (Hoboken) 2021 Mar 2:e1353. Epub 2021 Mar 2.

Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.

Background: Resveratrol (3, 5, 4 -trihydroxystilbene), a natural polyphenol and phytoalexin, has drawn considerable attention in the past decade due to its wide variety of therapeutic activities such as anticancer, anti-inflammatory, and antioxidant properties. However, its poor water solubility, low chemical stability, and short biological half-life limit its clinical utility.

Recent Findings: Nanoparticles overcome the limitations associated with conventional chemotherapeutic drugs, such as limited availability of drugs to the tumor tissues, high systemic exposures, and consequent toxicity to healthy tissues. This review focuses on the physicochemical properties of resveratrol, the therapeutic potential of resveratrol nano-formulations, and the anticancer activity of resveratrol encapsulated nanoparticles on various malignancies such as skin, breast, prostate, colon, liver, ovarian, and lung cancers (focusing on both in vitro and in vivo studies).

Conclusions: Nanotechnology approaches have been extensively utilized to achieve higher solubility, improved oral bioavailability, enhanced stability, and controlled release of resveratrol. The resveratrol nanoparticles have markedly enhanced its anticancer activity both in vitro and in vivo, thus considering it as a potential strategy to fight various cancers.
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http://dx.doi.org/10.1002/cnr2.1353DOI Listing
March 2021

The use of zebrafish model in prostate cancer therapeutic development and discovery.

Cancer Chemother Pharmacol 2021 Mar 3;87(3):311-325. Epub 2021 Jan 3.

Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH, USA.

Zebrafish is now among the leading in vivo model for cancer research, including prostate cancer. They are an alternative economic model being used to study cancer development, proliferation, and metastasis. They can also be effectively utilized for the development of cancer drugs at all levels, including target validation, and high-throughput screening for possible lead molecules. In this review, we provide a comprehensive overview of the role of zebrafish as an in vivo model in prostate cancer research. Globally, prostate cancer is a leading cause of death in men. Although many molecular mechanisms have been identified as playing a role in the pathogenesis of prostate cancer, there is still a significant need to understand the initial events of the disease. Furthermore, current treatments are limited by the emergence of severe toxicities and multidrug resistance. There is an essential need for economical and relevant research tools to improve our understanding and overcome these problems. This review provides a comprehensive summary of studies that utilized zebrafish for different aims in prostate cancer research. We discuss the use of zebrafish in prostate cancer cell proliferation and metastasis, defining signaling pathways, drug discovery and therapeutic development against prostate cancer, and toxicity studies. Finally, this review highlights limitations in this field and future directions to efficiently use zebrafish as a robust model for prostate cancer therapeutics development.
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http://dx.doi.org/10.1007/s00280-020-04211-zDOI Listing
March 2021

A Short Review on the Intranasal Delivery of Diazepam for Treating Acute Repetitive Seizures.

Pharmaceutics 2020 Nov 30;12(12). Epub 2020 Nov 30.

Department of Pharmacy Practice, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA.

Benzodiazepines such as diazepam, lorazepam and midazolam remained the mainstay of treatment for acute repetitive seizures (ARS). The immediate care for ARS should often begin at home by a caregiver. This prevents the progression of ARS to prolonged seizures or status epilepticus. For a long time and despite social objections rectal diazepam gel remained only FDA-approved rescue medication. Intranasal administration of benzodiazepines is considered attractive and safe compared with rectal, buccal and sublingual routes. Intranasal delivery offers numerous advantages such as large absorptive surface area, bypass the first-pass metabolism and good patient acceptance as it is needle free and painless. Recent clinical studies have demonstrated that diazepam nasal spray (NRL-1; Valtoco, Neurelis Inc.,San Diego, CA, USA) showed less pharmacokinetic variability and reliable bioavailability compared with the diazepam rectal gel. Diazepam nasal spray could be considered as a suitable alternative for treating seizure emergencies outside the hospital. This review summarizes the treatment options for ARS and findings from clinical studies involving intranasal diazepam for treating seizure emergencies.
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http://dx.doi.org/10.3390/pharmaceutics12121167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761129PMC
November 2020

Evaluation of Cytotoxicity and Taste-Masking Effect of Selected Flavors on Dental Lidocaine HCl Injection.

Pharmaceuticals (Basel) 2020 Oct 29;13(11). Epub 2020 Oct 29.

Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Health Science Campus, 3000 Arlington Ave, Toledo, OH 43614, USA.

Aim: Anxiety and intolerance to dental local anesthetic injections are common in patients undergoing dental procedures. This work was designed to study cytotoxicity of selected flavors in primary gingival keratinocytes (PGK), to acquire information on their suitability for use in dental lidocaine hydrochloride (LID) injection. We also evaluated the bio-mimetic taste of LID dental injection in the presence of selected flavors and sweetener using an Astree electronic tongue (ETongue).

Methods: The cytotoxicity of chocolate natural and artificial flavor (CTE), raspberry flavor artificial (RAS), cherry flavor (CHR), bitterness suppressor flavor (BSF) and lemon flavor extract (LFE) at various dilutions (0.16-10% /) was carried out in PGK using the live cell morphological analysis and MTT cell cytotoxicity assay. Based on the cytotoxicity data, CTE and RAS were added to Xylocaine (2%) along with 0.09% sodium saccharin and taste was assessed using an ETongue.

Results: After three hours of treatment, a dose-dependent cell death was induced by all flavors compared to the untreated control. BSF was found to be more toxic when compared to other flavors. CTE was found to be less toxic. The mean IC50 values of CTE, RAS, CHR, BSF and LFE in PGK were found to be 9.54, 8.43, 2.21, 0.38 and 4.01 mg/mL. Taste analysis with the ETongue showed a clear taste difference between the control and test formulations containing CTE and RAS flavors along with sodium saccharin.

Conclusion: CTE and RAS flavors in combination with 0.09% sodium saccharin can achieve a significant taste-masking effect in the dental LID injection.
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http://dx.doi.org/10.3390/ph13110353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693877PMC
October 2020

The Role of Nano-ophthalmology in Treating Dry Eye Disease.

Pharm Nanotechnol 2020 ;8(4):258-289

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates.

Dry eye disease (DED) is a common multifactorial disease linked to the tears/ocular surface leading to eye discomfort, ocular surface damage, and visual disturbance. Antiinflammatory agents (steroids and cyclosporine A), hormonal therapy, antibiotics, nerve growth factors, essential fatty acids are used as treatment options of DED. Current therapies attempt to reduce the ocular discomfort by producing lubrication and stimulating gland/nerve(s) associated with tear production, without providing a permanent cure for dry eye. Nanocarrier systems show a great promise to revolutionize drug delivery in DED, offering many advantages such as site specific and sustained delivery of therapeutic agents. This review presents an overview, pathophysiology, prevalence and etiology of DED, with an emphasis on preclinical and clinical studies involving the use of nanocarrier systems in treating DED. Lay Summary: Dry eye disease (DED) is a multifactorial disease associated with tear deficiency or excessive tear evaporation. There are several review articles that summarize DED, disease symptoms, causes and treatment approaches. Nanocarrier systems show a great promise to revolutionize drug delivery in DED, offering many advantages such as site specific and sustained delivery of therapeutic agents. Very few review articles summarize the findings on the use of nanotherapeutics in DED. In this review, we have exclusively discussed the preclinical and clinical studies of nanotherapeutics in DED therapy. This information will be attractive to both academic and pharmaceutical industry researchers working in DED therapeutics.
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http://dx.doi.org/10.2174/2211738508666200628034227DOI Listing
January 2020

Ultrasound-mediated topical delivery of econazole nitrate with potential for treating Raynaud's phenomenon.

Int J Pharm 2020 Apr 14;580:119229. Epub 2020 Mar 14.

Department of Medicine, Division of Rheumatology, University of Toledo, Toledo, USA.

The study aims to assess the ultrasound-assisted econazole nitrate (EN) permeation from topically applied formulations with potential for treating Raynaud's phenomenon. Optimization of ultrasound parameters such as the distance of the horn, application time and amplitude were performed. In vitro percutaneous absorption studies were performed using econazole formulations (F2_HPMC dispersion, F4_Lipoderm® Activemax™ Cream) across the ultrasound-treated porcine skin and were compared with the control group (skin samples without ultrasound). Histology and ATR-FTIR studies were performed on treated skin samples. A constant frequency (20 kHz) ultrasound application with 40% amplitude, 0.5 cm distance between ultrasound horn and the skin surface for 2 min was optimized. The permeation of EN was found to be higher from ultrasound-treated skin samples than the control group. Drug permeation from F2_HPMC dispersion was found to be higher as compared to the other formulations and the marketed EN cream. Histological evaluation confirmed that F2_HPMC dispersion showed no signs of toxicity. ATR-FTIR studies revealed a slight increase in the CH stretching vibrations (~2920 cm and 2850 cm) in ultrasound-treated skin samples as compared with the control. In conclusion, the ultrasound-assisted transdermal delivery of F2_HPMC dispersion could be further studied as a new therapy for Raynaud's phenomenon.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119229DOI Listing
April 2020

Alternatives to Biological Skin in Permeation Studies: Current Trends and Possibilities.

Pharmaceutics 2020 Feb 13;12(2). Epub 2020 Feb 13.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.

The transdermal route of drugs has received increased attention in recent years due to numerous advantages over the oral and injectable routes, such as avoidance of the hepatic metabolism, protection of drugs from the gastrointestinal tract, sustained drug delivery, and good patient compliance. The assessment of ex vivo permeation during the pharmaceutical development process helps in understanding the product quality and performance of a transdermal delivery system. Generally, excised human skin relevant to the application site or animal skin is recommended for ex vivo permeation studies. However, the limited availability of the human skin and ethical issues surrounding the use of animal skin rendered these models less attractive in the permeation study. In the last three decades, enormous efforts have been put into developing artificial membranes and 3D cultured human skin models as surrogates to the human skin. This manuscript provides an insight on the European Medicines Agency (EMA) guidelines for permeation studies and the parameters affected when using Franz diffusion cells in the permeation study. The need and possibilities for skin alternatives, such as artificially cultured human skin models, parallel artificial membrane permeability assays (PAMPA), and artificial membranes for penetration and permeation studies, are comprehensively discussed.
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http://dx.doi.org/10.3390/pharmaceutics12020152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076422PMC
February 2020

Flavonoids as Multi-Target Compounds: A Special Emphasis on their Potential as Chemo-adjuvants in Cancer Therapy.

Curr Pharm Des 2020 ;26(15):1712-1728

Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH 43606, United States.

Flavonoids are low molecular weight, polyphenolic phytochemicals, obtained from secondary metabolism of various plant compounds. They have a spectrum of pharmacological efficacies, including potential anticancer efficacy. Natural flavonoids are present in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. Flavonoids can attenuate or inhibit the initiation, promotion and progression of cancer by modulating various enzymes and receptors in diverse pathways that involve cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis. Furthermore, in vitro, flavonoids have been shown to reverse multidrug resistance when used as chemo-adjuvants. Flavonoids (both natural and synthetic analogues) interact with several oncogenic targets through dependent and independent mechanisms to mediate their anticancer efficacy in different types of cancer cells.
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http://dx.doi.org/10.2174/1381612826666200128095248DOI Listing
November 2020

Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells.

Cancers (Basel) 2019 May 23;11(5). Epub 2019 May 23.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.
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http://dx.doi.org/10.3390/cancers11050711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563099PMC
May 2019

Evaluation of topical econazole nitrate formulations with potential for treating Raynaud's phenomenon.

Pharm Dev Technol 2019 Jul 26;24(6):689-699. Epub 2019 Apr 26.

c Department of Medicine, Division of Rheumatology , University of Toledo , Toledo , OH , USA.

The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud's phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase cream, and F4Lipoderm Activemax™ Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10-20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2HPMC dispersion could be further explored as a treatment option for RP.
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http://dx.doi.org/10.1080/10837450.2019.1578371DOI Listing
July 2019

Biomedical Applications of Electrospun Nanofibers: Drug and Nanoparticle Delivery.

Pharmaceutics 2018 Dec 24;11(1). Epub 2018 Dec 24.

Department of Mechanical, Industrial and Manufacturing Engineering, University of Toledo, Toledo, OH 43614, USA.

The electrospinning process has gained popularity due to its ease of use, simplicity and diverse applications. The properties of electrospun fibers can be controlled by modifying either process variables (e.g., applied voltage, solution flow rate, and distance between charged capillary and collector) or polymeric solution properties (e.g., concentration, molecular weight, viscosity, surface tension, solvent volatility, conductivity, and surface charge density). However, many variables affecting electrospinning are interdependent. An optimized electrospinning process is one in which these parameters remain constant and continuously produce nanofibers consistent in physicochemical properties. In addition, nozzle configurations, such as single nozzle, coaxial, multi-jet electrospinning, have an impact on the fiber characteristics. The polymeric solution could be aqueous, a polymeric melt or an emulsion, which in turn leads to different types of nanofiber formation. Nanofiber properties can also be modified by polarity inversion and by varying the collector design. The active moiety is incorporated into polymeric fibers by blending, surface modification or emulsion formation. The nanofibers can be further modified to deliver multiple drugs, and multilayer polymer coating allows sustained release of the incorporated active moiety. Electrospun nanofibers prepared from polymers are used to deliver antibiotic and anticancer agents, DNA, RNA, proteins and growth factors. This review provides a compilation of studies involving the use of electrospun fibers in biomedical applications with emphasis on nanoparticle-impregnated nanofibers.
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http://dx.doi.org/10.3390/pharmaceutics11010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358861PMC
December 2018

Imaging Techniques in the Diagnosis and Management of Ocular Tumors: Prospects and Challenges.

AAPS J 2018 09 5;20(6):97. Epub 2018 Sep 5.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P.O. Box 346, Ajman, United Arab Emirates.

Different types of imaging modalities are used in the diagnosis of ocular cancer. Selection of an imaging modality is based on the features of a tumor as well as the inherent characteristics of the imaging technique. It is vital to select an appropriate imaging modality in diagnosis of ocular tumor with confidence. This review focuses on five most commonly used imaging modalities, i.e., positron emission tomography-computed tomography (PET/CT), single photon emission computed tomography (SPECT), optical coherence tomography (OCT), ultrasound (US), and magnetic resonance imaging (MRI). The principal of imaging modalities is briefly explained, along with their role in the diagnosis and management of the most common ocular tumors such as retinoblastoma and uveal melanoma. Further, the diagnostic features of ocular tumors corresponding to each imaging modality and possibilities of utilizing imaging techniques in the process of ocular drug development are included in this review.
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http://dx.doi.org/10.1208/s12248-018-0259-9DOI Listing
September 2018

FSE-Ag complex NS: preparation and evaluation of antibacterial activity.

IET Nanobiotechnol 2018 Sep;12(6):836-840

School of Pharmacy, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968, USA.

Silver (Ag) complexes of drugs and their nanosystems have great potential as antibacterials. Recently, an Ag complex of furosemide (Ag-FSE) has shown to be a promising antimicrobial. However, poor solubility of Ag-FSE could hamper its introduction into clinics. Therefore, the authors developed a nanosuspension of Ag-FSE (Ag-FSE_NS) for its solubility and antibacterial activity enhancement. The aim of this study was to introduce a novel nanoantibiotic with enhanced antibacterial efficacy. Ag-FSE_NS was prepared by precipitation-ultrasonication technique. Size, polydispersity index (PI) and zeta potential (ZP) of prepared Ag-FSE_NS were measured by dynamic light scattering, whereas surface morphology was determined using scanning electron microscopy (SEM). antibacterial activity was evaluated against , and using broth microdilution method. Size, PI and ZP of optimised Ag-FSE_NS1 were 191.2 ± 19.34 nm, 0.465 ± 0.059 and -55.7 ± 8.18 mV, respectively. SEM revealed that Ag-FSE_NS1 particles were rod or needle-like with smooth surfaces. Saturation solubility of Ag-FSE in NS increased eight-fold than pure Ag-FSE. Ag-FSE_NS1 exhibited two-fold and eight-fold enhancements in activity against and , respectively. The results obtained showed that developed Ag-FSE_NS1 holds a promise as a topical antibacterial.
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http://dx.doi.org/10.1049/iet-nbt.2017.0284DOI Listing
September 2018

Physical compatibility of milrinone with levofloxacin and ceftriaxone injection.

Am J Health Syst Pharm 2018 07;75(14):1010-1012

College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledo, OH.

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http://dx.doi.org/10.2146/ajhp180195DOI Listing
July 2018

Elucidation of the orientation of selected drugs with 2-hydroxylpropyl-β-cyclodextrin using 2D-NMR spectroscopy and molecular modeling.

Int J Pharm 2018 Jul 7;545(1-2):357-365. Epub 2018 May 7.

Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, OH 43614, USA. Electronic address:

This project aims to study the nature of interaction and orientation of selected drugs such as dexamethorphan HBr (DXM), diphenhydramine HCl (DPH), and lidocaine HCl (LDC) inclusion complexes with hydroxyl-propyl ß-cyclodextrin (HP-ß-CD) using HNMR spectroscopy, 2D-NMR ROESY and molecular-modeling techniques. Freeze-drying technique was used to formulate the inclusion complexes between DXM, DPH and LDC with HP-ß-CD (1:1 M ratio) in solid state. Inclusion complex formation was initially characterized by Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Further characterization of inclusion complexes to determine the interaction of DXM, DPH and LDC with HP-β-CD was performed using the HNMR spectroscopy, 2D-NMR ROESY and molecular modeling techniques. Inclusion complexes of DXM, DPH and LDC with HP-ß-CD were successfully prepared using the freeze-drying technique. Preliminary studies with FT-IR, DSC, XRD and SEM indicated the formation of inclusion complexes of DXM, DPH and LDC with HP-β-CD at 1:1 M ratio. HNMR study showed a change in proton chemical shift upon complexation. 2D-NMR ROESY (two-dimensional) spectroscopy gave an insight into the spatial arrangement between the host and guest atoms. 2D-ROESY experiments further predicted the direction of orientation of guest molecules, indicating the probability that amino moieties of DXM, DPH and LDC are inside the hydrophobic HP-ß-CD cavity. Cross-peaks of inclusion complexes demonstrated intermolecular nuclear Overhauser effects (NOE) between the amino protons in DXM, DPH and LDC and H-atoms of HP-ß-CD. Molecular modeling studies further confirmed the NMR data, providing a structural basis of the individual complex formations. Microsecond time-level molecular dynamics and metadynamics simulations indicate much stronger binding of DXM to HP-ß-CD and more dynamic behavior for DPH and LDC. In particular, LDC can exhibit multiple binding modes, and even spent some time (∼1-2%) out of the carrier, proving the dynamic nature of the complex. To conclude, 2D-NMR and molecular dynamic simulations elucidate the formation of inclusion complexes and intermolecular interactions of DXM, DPH and LDC with HP-ß-CD.
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http://dx.doi.org/10.1016/j.ijpharm.2018.05.016DOI Listing
July 2018

Physical compatibility of levetiracetam injection with heparin, dobutamine, and dopamine.

Am J Health Syst Pharm 2018 04;75(8):510-512

College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledo, OH.

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http://dx.doi.org/10.2146/ajhp180069DOI Listing
April 2018

Ocular Drug Delivery Barriers-Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases.

Pharmaceutics 2018 Feb 27;10(1). Epub 2018 Feb 27.

College of Pharmacy and Pharmaceutical Sciences, The University of Toledo Health Science Campus, Toledo, OH 43614, USA.

Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed.
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http://dx.doi.org/10.3390/pharmaceutics10010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874841PMC
February 2018

Development and Evaluation of a Novel Microemulsion of Dexamethasone and Tobramycin for Topical Ocular Administration.

J Ocul Pharmacol Ther 2018 05 6;34(4):312-324. Epub 2018 Feb 6.

Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo Health Science Campus, The University of Toledo , Toledo, Ohio.

Purpose: The purpose of this study was to develop and evaluate a novel dexamethasone- and tobramycin-loaded microemulsion for its potential for treating anterior segment eye infections.

Methods: The microemulsion was evaluated for pH, particle size, zeta potential, light transmittance, morphology, and in vitro drug release. Sterility of the microemulsion was evaluated by direct as well as plate inoculation methods. Anti-inflammatory activity of dexamethasone, bactericidal activity of tobramycin, and cytotoxicity of the microemulsion were assessed and compared to that of the marketed eye drop suspension (Tobradex). Histological evaluation was performed in bovine corneas to assess the safety of microemulsion in comparison to Tobradex suspension. In addition, the stability of the microemulsion was studied at 4°C, 25°C, and 40°C.

Results: The pH of the microemulsion was close to the pH of tear fluid. The microemulsion displayed an average globule size under 20 nm, with light transmittance around 95%-100%. The aseptically prepared microemulsion remained sterile for up to 14 days. The cytotoxicity of the microemulsion in bovine corneal endothelial cells was comparable to that of the Tobradex suspension. The anti-inflammatory activity of dexamethasone and the antibacterial activity of tobramycin from the microemulsion were significantly higher than those of the Tobradex suspension (P < 0.05). Histological evaluation showed an intact corneal epithelium without any signs of toxicity, and the developed microemulsion was found to be stable at 4°C and 25°C for 3 months.

Conclusion: In conclusion, the developed microemulsion could be explored as a suitable alternative to the marketed suspension for treating anterior segment eye infections.
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http://dx.doi.org/10.1089/jop.2017.0082DOI Listing
May 2018

Comparison of electrospun and solvent cast polylactic acid (PLA)/poly(vinyl alcohol) (PVA) inserts as potential ocular drug delivery vehicles.

Mater Sci Eng C Mater Biol Appl 2017 Aug 1;77:895-903. Epub 2017 Apr 1.

College of Pharmacy and Pharmaceutical Sciences, The University of Toledo Health Science Campus, Toledo, OH 43614, USA. Electronic address:

Purpose: The purpose of this work was to develop, characterize and compare electrospun nanofiber inserts (ENIs) and solvent cast polymeric inserts (SCIs) for ocular drug delivery.

Methods: ENI and SCI of 1%, 5% and 10% w/w dexamethasone were fabricated using a blend of poly-lactic acid (PLA) and poly-vinyl alcohol (PVA). Inserts were characterized for morphology, thickness, pH, drug content, drug crystallinity, in vitro drug release, sterility, dimethylformamide (DMF) and chloroform content, and cytotoxicity.

Results: The thickness of 1%, 5%, and 10% dexamethasone-loaded ENIs were found to be 50μm, 62.5μm, and 93.3μm, respectively, with good folding endurance. SCIs were brittle, with thickness values >200μm. Drug release rates from 1%, 5% and 10% ENIs were found to be 0.62μg/h, 1.46μg/h, and 2.30μg/h, respectively, while those from SCIs were erratic. DMF content in ENIs and SCIs were 0.007% w/w and 0.123% w/w, respectively, while chloroform was not detected. No cytotoxicity was observed from ENIs in cultured bovine corneal endothelial cells for up to 24h.

Conclusion: We conclude that ENIs are better than SCIs and could be utilized as a potential delivery system for treating anterior segment ocular diseases.
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http://dx.doi.org/10.1016/j.msec.2017.03.305DOI Listing
August 2017

Physical compatibility of valproate sodium injection with dobutamine and dopamine.

Am J Health Syst Pharm 2017 03;74(5):280-281

College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledo, OH.

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http://dx.doi.org/10.2146/ajhp160924DOI Listing
March 2017

Dry Eye Disease: Present Challenges in the Management and Future Trends.

Curr Pharm Des 2016 ;22(28):4470-90

Department of Pharmacy Practice, The University of Toledo HSC, College of Pharmacy and Pharmaceutical Sciences, 3000 Arlington Ave. (MS1013), Toledo, OH 43614.

Dry eye disease (DED) is a tear film disorder resulting in hyperosmolarity of the tear film and inflammation of the ocular surface. DED is also referred to as keratoconjunctivitis sicca (KCS) and dry eye syndrome. DED represents a significant public health issue, particularly in older adults, and needs more research and attention. Despite the urgent need for safe and effective pharmacotherapies, there is currently only one approved medication, Restasis®, to tackle DED. In this review article, we present an overview of DED, classification, epidemiology, pathophysiology, diagnosis, and risk factors of DED. Special emphasis is placed on current treatment options for DED such as artificial tears, lipid-containing lubricants, liposomal spray, inserts, anti-inflammatory or immunosuppressant drops, antibiotics, dietary omega-3 essential fatty acids, autologous serum, intense-pulsed-light (IPL), punctual plugs, moisture-retaining eyeglasses, hydrophilic bandage contact lenses and secretagogues. The review also summarizes trends in DED treatment that are patented and are currently under investigation in clinical trials.
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http://dx.doi.org/10.2174/1381612822666160614012634DOI Listing
March 2018

Formulation and In Vitro Evaluation of Cyclosporine-A Inserts Prepared Using Hydroxypropyl Methylcellulose for Treating Dry Eye Disease.

J Ocul Pharmacol Ther 2016 09 13;32(7):451-62. Epub 2016 Jun 13.

Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo Health Science Campus , Toledo, Ohio.

Purpose: The aim of this study was to develop and characterize a novel sustained-release drug delivery system of cyclosporine-A (CsA) using hydroxypropyl methylcellulose (HPMC) and xanthan gum (XG) for treating dry eye disease (DED).

Methods: Polymeric inserts of CsA were prepared using the solvent casting technique with a 2(3) full factorial design to evaluate the effect of HPMC and XG ratios and drug content on thickness, folding endurance, wettability, and in vitro drug release. Inserts were also evaluated for drug content, moisture absorption and loss, and surface pH. Inserts with an optimized ratio of HPMC and XG were sterilized with UV light and evaluated for morphology, thermal analysis, Fourier transform infrared spectroscopy, stability at 4°C, 25°C, and 40°C, cytotoxicity in cultured bovine corneal endothelial cells, and anti-inflammatory effect in Jurkat T cells.

Results: The addition of XG increased the CsA release duration and enhanced the folding endurance of films. All films showed uniformity in drug content and thickness. Formulation F4 composed of 1% HPMC and 0.25% XG exhibited good folding endurance and sustained CsA release for up to 20 h. Sterility testing of F4 using plate and direct inoculation confirmed the formulation sterility and validated the sterilization method. The formulation was stable for at least 3 months at 4°C, 25°C, and 40°C. No cytotoxicity was observed in cultured bovine corneal endothelial cells for up to 24 h. The anti-inflammatory effect of CsA was intact in ophthalmic inserts.

Conclusion: In conclusion, combination therapy with HPMC and CsA can be a potential once-a-day formulation for treating DED.
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http://dx.doi.org/10.1089/jop.2016.0013DOI Listing
September 2016

Assessing development in critical thinking: One institution's experience.

Curr Pharm Teach Learn 2016 May - Jun;8(3):271-278. Epub 2016 Mar 22.

University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH.

Objective: Enhancing critical and moral thinking are goals of higher education. We sought to examine thinking development within a Doctor of Pharmacy (Pharm.D.) program.

Methods: The California Critical Thinking Skills Test (CCTST), Health Sciences Reasoning Test (HSRT), and the Defining Issues Test (DIT2) were administered to Pharm.D. students over four sessions throughout their didactic studies. Students took tests in their P1 Fall, P1 Spring, P2 Spring, and P3 Spring. While CCTST and HSRT are similar for assessing foundational critical thinking, the DIT2 assesses complex moral thinking. Each thinking test was correlated with academic success by undergraduate and graduate grade-point averages (GPAs).

Results: The CCTST was administered in P1 Fall (20.1 ± 5.0). For HSRT, mean ± S.D. was P1 Spring: 22.7 ± 3.5, P2 Spring: 22.6 ± 4.8, and P3 Spring: 23.8 ± 4.5. After converting P1-CCTST and P2-HSRT scores using user-manual interpretations, there was no difference on paired comparison (P = 0.22, 0.1 Cohen's d). There was a small difference between P1-HSRT and P3-HSRT (P < 0.01, 0.2 Cohen's d). Also administered each time, the DIT2 was P1 Fall: 40.4 ± 12.6, P1 Spring: 36.3 ± 13.7, P2 Spring: 44.9 ± 13.6, and P3 Spring: 43.4 ± 15.4. For DIT2, both P1 Fall to P2 Spring and P1 Spring to P3 Spring were significant with small and medium effect-sizes (both P < 0.01, 0.4 and 0.5 Cohen's d respectively). Importantly, multiple HSRT, and DIT2 assessments correlated with undergraduate and graduate GPAs.

Conclusions: During a Pharm.D. program of study, students developed substantially in moral reasoning though minimally in foundational critical thinking. Both foundational and moral reasoning correlated with academic success. Showing responsiveness to change, the DIT2 appears helpful as a measure of cognitive development for pharmacy education.
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http://dx.doi.org/10.1016/j.cptl.2016.02.007DOI Listing
March 2016

Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin.

Drug Dev Ind Pharm 2016 Aug 21;42(8):1258-66. Epub 2015 Dec 21.

a Department of Pharmacy Practice , College of Pharmacy and Pharmaceutical Sciences, The University of Toledo , Toledo, OH , USA.

Objective: The overall objective of this work is to determine the percutaneous absorption of chlorpromazine hydrochloride from pluronic lecithin organogels (PLO gels) and verify the suitability of topically applied chlorpromazine hydrochloride PLO gels for use in hospice patients for relieving symptoms such as vomiting and nausea during the end stages of life.

Methods: PLO gels of chlorpromazine hydrochloride were prepared using isopropyl palmitate (IPP) or ricinoleic acid (RA) as oil phase. In vitro percutaneous absorption of chlorpromazine hydrochloride was assessed through porcine ear and human abdominal skin. Further, the theoretical steady state plasma concentration (Css) of chlorpromazine was calculated from the flux values.

Results: The pH, viscosity, and stability of both PLO gels prepared with IPP and RA were comparable. The thixotropic property of RA PLO gel was found to be better than that of IPP PLO gel. The permeation of chlorpromazine hydrochloride was higher from RA PLO gel than from IPP PLO gel and pure drug solution. Theoretical Css of chlorpromazine from pure drug solution, IPP PLO gel and RA PLO gel were found to be 1.05, 1.20, and 1.50 ng/ml, respectively. PLO gels only marginally increased the flux and theoretical Css of chlorpromazine.

Conclusion: From this study, it is clearly evident that PLO gels fail to achieve required systemic levels of chlorpromazine following topical application. Chlorpromazine PLO gel may not be effective in treating nausea and vomiting for hospice patients with swallowing difficulties.
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http://dx.doi.org/10.3109/03639045.2015.1122610DOI Listing
August 2016

Development and evaluation of dexamethasone nanomicelles with potential for treating posterior uveitis after topical application.

J Ocul Pharmacol Ther 2015 May 3;31(4):215-27. Epub 2015 Apr 3.

1 Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo , Toledo, Ohio.

Purpose: This study aims at the development and preliminary evaluation of dexamethasone nanomicelles for treating posterior uveitis. Nanomicelles were formulated using polyoxyl 40 stearate (P40S) and polysorbate 80 (P80), which are approved by the FDA for ocular use.

Methods: Dexamethasone nanomicelles were prepared and characterized for critical micellar concentration, solubility of dexamethasone, particle size, surface charge, morphology, in vitro drug release, clarity, stability, filtration efficiency, and sterility. Ocular tolerance and the tissue drug distribution of dexamethasone were assessed in rabbits after single and multiple topical administration.

Results: Dexamethasone nanomicelles (0.1% w/v) were successfully developed and characterized with an optimized composition of P40S/P80=7/3 by weight. The mean diameter of blank and drug-loaded nanomicelles was 13.3±0.4 and 14.5±0.4 nm, respectively. Transmission electron microscopy images revealed the spherical structure of nanomicelles. Nanomicelles were found to be stable with respect to clarity, size and drug content at 4°C and 25°C for up to 6 months. No irritation or redness was observed in the treated eyes as compared with the untreated control rabbit eyes. Therapeutic concentrations of dexamethasone were observed in the retina and choroid after single and multiple topical application in rabbits.

Conclusion: In conclusion, the nanomicelles of P40S and P80 could efficiently solubilize 0.1% dexamethasone in their cores. The results also indicate that mixed nanomicelles could be utilized as a potential delivery system for delivering dexamethasone to treat the back of the eye diseases such as posterior uveitis after topical application.
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http://dx.doi.org/10.1089/jop.2014.0152DOI Listing
May 2015

Development and characterization of erythrosine nanoparticles with potential for treating sinusitis using photodynamic therapy.

Photodiagnosis Photodyn Ther 2015 Mar 25;12(1):9-18. Epub 2015 Jan 25.

College of Pharmacy and Pharmaceutical Sciences, The University of Toledo Health Science Campus, Toledo, OH 43614, United States. Electronic address:

Background: Antimicrobial therapy for sinusitis has been shown to reduce or eliminate pathologic bacteria associated with rhinosinusitis and improve the symptoms associated with the disease. However, the continuing rise in antibiotic resistance, the ongoing problem with patient compliance, and the intrinsic difficulty in eradication of biofilms complicates antibiotic therapy. The introduction of photodynamic antimicrobial therapy (PAT) using erythrosine, a photosensitizer, could eliminate the bacteria without inducing antibiotic resistance or even requiring daily dosing. In the present study, erythrosine nanoparticles were prepared using poly-lactic-co-glycolic acid (PLGA) and evaluated for their potential in PAT against Staphylococcus aureus cells.

Methods: PLGA nanoparticles of erythrosine were prepared by nanoprecipitation technique. Erythrosine nanoparticles were characterized for size, zeta potential, morphology and in vitro release. Qualitative and quantitative uptake studies of erythrosine nanoparticles were carried out in S. aureus cells. Photodynamic inactivation of S. aureus cells in the presence of erythrosine nanoparticles was investigated by colony forming unit assay.

Results: Nanoprecipitation technique resulted in nanoparticles with a mean diameter of 385nm and zeta potential of -9.36mV. Erythrosine was slowly released from nanoparticles over a period of 120h. The qualitative study using flow cytometry showed the ability of S. aureus cells to internalize erythrosine nanoparticles. Moreover, erythrosine nanoparticles exhibited a significantly higher uptake and antimicrobial efficacy compared to pure drug in S. aureus cells.

Conclusion: In conclusion, erythrosine-loaded PLGA nanoparticles can be a potential long term drug delivery system for PAT and are useful for the eradication of S. aureus cells.
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http://dx.doi.org/10.1016/j.pdpdt.2015.01.005DOI Listing
March 2015

Anti-inflammatory effects of a novel ricinoleic acid poloxamer gel system for transdermal delivery.

Int J Pharm 2015 Feb 24;479(1):207-11. Epub 2014 Dec 24.

Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210, USA.

Our previous study showed that the use of ricinoleic acid as an oil phase resulted in the formation of a stable pluronic lecithin organogel (PLO gel) with better thixotropic properties and higher permeation of ketoprofen than the isopropyl palmitate PLO gel. This study aims to evaluate and compare the in vitro and in vivo anti-inflammatory effects of the ricinoleic acid PLO gel system with isopropyl palmitate PLO gel. Ketoprofen was used as a model drug. In vitro anti-inflammatory activity and cell viability tests were performed in human rheumatoid arthritis synovial fibroblast cell line using a blank ricinoleic acid PLO gel and compared to that of the isopropyl palmitate PLO gel. In vivo anti-inflammatory activity of ricinoleic acid PLO gel containing 10% ketoprofen was evaluated and compared with the isopropyl palmitate PLO gel in a carrageenan-induced rat paw edema model. The results from the in vitro study showed that the blank ricinoleic acid PLO gel possessed significantly higher anti-inflammatory activity than isopropyl palmitate PLO gel at 1 mM concentration (p<0.05), while both the gel formulations had no significant cytotoxic activity. Further in vivo testing of the formulation showed that the ricinoleic acid PLO gel formulation was significantly more effective in reducing pain and edema when compared to the isopropyl palmitate PLO gel. In addition, the ricinoleic acid PLO gel formulation markedly inhibited the synthesis of prostaglandin E2. In conclusion, the efficacy of PLO gels used in pain management may be enhanced by using ricinoleic acid instead of isopropyl palmitate as an oil phase.
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http://dx.doi.org/10.1016/j.ijpharm.2014.12.051DOI Listing
February 2015

Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats.

Front Behav Neurosci 2014 30;8:366. Epub 2014 Oct 30.

Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Toledo, OH, USA.

We have recently shown that upregulation of glutamate transporter 1 (GLT1) in the brain is associated in part with reduction in ethanol intake in alcohol-preferring (P) male rats. In this study, we investigated the effects of a synthetic compound, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), known to activate GLT1 on ethanol consumption as well as GLT1 expression and certain signaling pathways in P rats. P rats were given 24-h concurrent access to 15 and 30% ethanol, water and food for 5 weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for 5 consecutive days. We also tested the effect of MS-153 on daily sucrose (10%) intake. Our studies revealed a significant decrease in ethanol intake at the dose of 50 mg/kg MS-153 from Day 1 through 14. In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake. Importantly, we found that MS-153 upregulated the GLT1 level in the nucleus accumbens (NAc) but not in the prefrontal cortex (PFC). In accordance, we found upregulation of nuclear NFkB-65 level in NAc in MS-153-treated group, however, IkBα was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkBα levels in PFC. Interestingly, we revealed that p-Akt was downregulated in ethanol vehicle treated groups in the NAc; this downregulation was reversed by MS-153 treatment. We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups. These findings reveal MS-153 as a GLT1 modulator that may have potential as a therapeutic drug for the treatment of alcohol dependence.
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http://dx.doi.org/10.3389/fnbeh.2014.00366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214358PMC
November 2014

Masking the bitter taste of injectable lidocaine HCl formulation for dental procedures.

AAPS PharmSciTech 2015 Apr 1;16(2):455-65. Epub 2014 Nov 1.

College of Pharmacy and Pharmaceutical Sciences, The University of Toledo HSC, 3000 Arlington Ave. (MS1013), Toledo, Ohio, 43614, USA.

Several attempts have been made to mask the bitter taste of oral formulations, but none have been made for injectable formulations. This study aims to mask the bitter taste of dental lidocaine HCl (LID) injection using hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium saccharin. Inclusion complexes of LID and HP-β-CD were prepared by the solution method in 1:1 and 1:2 M ratios. Inclusion complexes in solution were studied using phase solubility in phosphate buffer solutions (pH 8, 9, and 10). Freeze-dried inclusion complexes were characterized using differential scanning calorimetry (DSC), X-ray, Fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR), scanning electron microscopy (SEM), and in vitro release. Injectable formulations were prepared using inclusion complexes and characterized for stability and for taste using an Alpha MOS ASTREE electronic tongue (ETongue). The association constants of HP-β-CD with lidocaine-free base and its ionized form were found to be 26.23 ± 0.00025 and 0.8694 ± 0.00045 M(-1), respectively. Characterization studies confirmed the formation of stable inclusion complexes of LID and HP-β-CD. Injectable formulations were found to be stable for up to 6 months at 4°C, 25°C, and 40°C. The taste evaluation study indicated that HP-β-CD (1:1 and 1:2 M ratios) significantly improved the bitter taste of LID injectable formulation. In conclusion, inclusion complex in the 1:1 M ratio with 0.09% sodium saccharin was considered to be optimum in masking the bitter taste of LID.
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http://dx.doi.org/10.1208/s12249-014-0239-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370974PMC
April 2015

Compatibility of argatroban injection with select antiarrhythmic drugs.

Am J Health Syst Pharm 2014 Nov;71(21):1831-2

College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledo, OH.

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http://dx.doi.org/10.2146/ajhp140258DOI Listing
November 2014