Pharmaceutics

101 KiB

Open AccessArticle

Interactions of Tenofovir, Lamivudine, Abacavir and Didanosine in Primary Human Cells

by Omar Janneh and Saye H. Khoo

Pharmaceutics 2011, 3(2), 326-337; https://doi.org/10.3390/pharmaceutics3020326 - 22 Jun 2011

Cited by 6 | Viewed by 6273

Certain triple nucleoside/tide reverse transcriptase inhibitor (NRTI) regimens containing tenofovir (TDF) have been associated with rapid early treatment failure. The mechanism is unknown, but may be at the level of drug transport. We measured the lipophilicity of the drugs [³H]-lamivudine (3TC), [...] Read more.

Certain triple nucleoside/tide reverse transcriptase inhibitor (NRTI) regimens containing tenofovir (TDF) have been associated with rapid early treatment failure. The mechanism is unknown, but may be at the level of drug transport. We measured the lipophilicity of the drugs [³H]-lamivudine (3TC), -didanosine (ddI), -TDF and -ABC. Peripheral blood mononuclear cells (PBMCs) were used to evaluate drug–drug interactions at the level of drug transport. PBMCs were measured for the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP) by flow cytometry. The rank order of the lipophilicity of the drugs were ABC>>>3TC³ddI>TDF. The accumulation of [³H]-3TC, -ddI and -TDF were temperature sensitive (suggesting facilitated transport), in contrast to [³H]-ABC. ABC reduced the accumulation of [³H]-3TC, and cell fractionation experiments suggested this was mainly in membrane-bound [³H]-3TC. ABC/TDF and ABC/ddI increased the accumulation of [³H]-3TC and 3TC/TDF also increased the accumulation of [³H]-TDF. In contrast, none of the NRTI/NtRTI incubations (alone or in combination) altered the accumulation of [³H]-ABC and -ddI. PBMC expression of P-gp, MRP1 and BCRP were detected, but none correlated with the accumulation of the drugs. The high failure rates seen with TDF, ABC and 3TC are not fully explained by an interaction at transporter level. Full article

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272 KiB

Open AccessArticle

In Vitro Dissolution Methods for Hydrophilic and Hydrophobic Porous Silicon Microparticles

by Juha Mönkäre, Joakim Riikonen, Elina Rauma, Jarno Salonen, Vesa-Pekka Lehto and Kristiina Järvinen

Pharmaceutics 2011, 3(2), 315-325; https://doi.org/10.3390/pharmaceutics3020315 - 21 Jun 2011

Cited by 10 | Viewed by 9253

Abstract

Porous silicon (PSi) is an innovative inorganic material that has been recently developed for various drug delivery systems. For example, hydrophilic and hydrophobic PSi microparticles have been utilized to improve the dissolution rate of poorly soluble drugs and to sustain peptide delivery. Previously, [...] Read more.

Porous silicon (PSi) is an innovative inorganic material that has been recently developed for various drug delivery systems. For example, hydrophilic and hydrophobic PSi microparticles have been utilized to improve the dissolution rate of poorly soluble drugs and to sustain peptide delivery. Previously, the well-plate method has been demonstrated to be a suitable in vitro dissolution method for hydrophilic PSi particles but it was not applicable to poorly wetting hydrophobic thermally hydrocarbonized PSi (THCPSi) particles. In this work, three different in vitro dissolution techniques, namely centrifuge, USP Apparatus 1 (basket) and well-plate methods were compared by using hydrophilic thermally carbonized PSi (TCPSi) microparticles loaded with poorly soluble ibuprofen or freely soluble antipyrine. All the methods showed a fast and complete or nearly complete release of both model compounds from the TCPSi microparticles indicating that all methods described in vitro dissolution equally. Based on these results, the centrifuge method was chosen to study the release of a peptide (ghrelin antagonist) from the THCPSi microparticles since it requires small sample amounts and achieves good particle suspendability. Sustained peptide release from the THCPSi microparticles was observed, which is in agreement with an earlier in vivo study. In conclusion, the centrifuge method was demonstrated to be a suitable tool for the evaluation of drug release from hydrophobic THCPSi particles, and the sustained peptide release from THCPSi microparticles was detected. Full article

(This article belongs to the Special Issue Recent Developments and Future Perspectives in Dissolution Testing)

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418 KiB

Open AccessArticle

Influence of the Vehicle on the Penetration of Particles into Hair Follicles

by Alexa Patzelt, Heike Richter, Lars Dähne, Peter Walden, Karl-Heinz Wiesmüller, Ute Wank, Wolfram Sterry and Jürgen Lademann

Pharmaceutics 2011, 3(2), 307-314; https://doi.org/10.3390/pharmaceutics3020307 - 14 Jun 2011

Cited by 25 | Viewed by 7510

Abstract

Recently, it has been demonstrated that particulate substances penetrate preferentially into the hair follicles and that the penetration depth depends on the particle size. In the present study, the influence of the vehicle of the particulate substances on the penetration depth was investigated. [...] Read more.

Recently, it has been demonstrated that particulate substances penetrate preferentially into the hair follicles and that the penetration depth depends on the particle size. In the present study, the influence of the vehicle of the particulate substances on the penetration depth was investigated. Four different formulations (ethanolic suspension, aqueous suspension, ethanolic gel and aqueous gel) containing peptide-loaded particles of 1 µm in diameter were prepared and applied on porcine ear skin. After penetration, punch biopsies were taken and the penetration depths of the particles were investigated by laser scanning microscopy. The deepest penetration was achieved with the gel formulations demonstrating an influence of the vehicle on the penetration depth of particulate substances. Full article

(This article belongs to the Special Issue Colloidal Drug Carrier Systems)

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2207 KiB

Open AccessArticle

Semi-solid Sucrose Stearate-Based Emulsions as Dermal Drug Delivery Systems

by Victoria Klang, Julia C. Schwarz, Nadejda Matsko, Elham Rezvani, Nivine El-Hagin, Michael Wirth and Claudia Valenta

Pharmaceutics 2011, 3(2), 275-306; https://doi.org/10.3390/pharmaceutics3020275 - 30 May 2011

Cited by 36 | Viewed by 12179

Abstract

Mild non-ionic sucrose ester surfactants can be employed to produce lipid-based drug delivery systems for dermal application. Moreover, sucrose esters of intermediate lipophilicity such as sucrose stearate S-970 possess a peculiar rheological behavior which can be employed to create highly viscous semi-solid formulations [...] Read more.

Mild non-ionic sucrose ester surfactants can be employed to produce lipid-based drug delivery systems for dermal application. Moreover, sucrose esters of intermediate lipophilicity such as sucrose stearate S-970 possess a peculiar rheological behavior which can be employed to create highly viscous semi-solid formulations without any further additives. Interestingly, it was possible to develop both viscous macroemulsions and fluid nanoemulsions with the same chemical composition merely by slight alteration of the production process. Optical light microscopy and cryo transmission electron microscopy (TEM) revealed that the sucrose ester led to the formation of an astonishing hydrophilic network at a concentration of only 5% w/w in the macroemulsion system. A small number of more finely structured aggregates composed of surplus surfactant were likewise detected in the nanoemulsions. These discoveries offer interesting possibilities to adapt the low viscosity of fluid O/W nanoemulsions for a more convenient application. Moreover, a simple and rapid production method for skin-friendly creamy O/W emulsions with excellent visual long-term stability is presented. It could be shown by franz-cell diffusion studies and in vitro tape stripping that the microviscosity within the semi-solid formulations was apparently not influenced by their increased macroviscosity: the release of three model drugs was not impaired by the complex network-like internal structure of the macroemulsions. These results indicate that the developed semi-solid emulsions with advantageous application properties are highly suitable for the unhindered delivery of lipophilic drugs despite their comparatively large particle size and high viscosity. Full article

(This article belongs to the Special Issue Colloidal Drug Carrier Systems)

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5913 KiB

Open AccessReview

Fluorescence Molecular Tomography: Principles and Potential for Pharmaceutical Research

by Florian Stuker, Jorge Ripoll and Markus Rudin

Pharmaceutics 2011, 3(2), 229-274; https://doi.org/10.3390/pharmaceutics3020229 - 26 Apr 2011

Cited by 127 | Viewed by 16283

Abstract

Fluorescence microscopic imaging is widely used in biomedical research to study molecular and cellular processes in cell culture or tissue samples. This is motivated by the high inherent sensitivity of fluorescence techniques, the spatial resolution that compares favorably with cellular dimensions, the stability [...] Read more.

Fluorescence microscopic imaging is widely used in biomedical research to study molecular and cellular processes in cell culture or tissue samples. This is motivated by the high inherent sensitivity of fluorescence techniques, the spatial resolution that compares favorably with cellular dimensions, the stability of the fluorescent labels used and the sophisticated labeling strategies that have been developed for selectively labeling target molecules. More recently, two and three-dimensional optical imaging methods have also been applied to monitor biological processes in intact biological organisms such as animals or even humans. These whole body optical imaging approaches have to cope with the fact that biological tissue is a highly scattering and absorbing medium. As a consequence, light propagation in tissue is well described by a diffusion approximation and accurate reconstruction of spatial information is demanding. While in vivo optical imaging is a highly sensitive method, the signal is strongly surface weighted, i.e., the signal detected from the same light source will become weaker the deeper it is embedded in tissue, and strongly depends on the optical properties of the surrounding tissue. Derivation of quantitative information, therefore, requires tomographic techniques such as fluorescence molecular tomography (FMT), which maps the three-dimensional distribution of a fluorescent probe or protein concentration. The combination of FMT with a structural imaging method such as X-ray computed tomography (CT) or Magnetic Resonance Imaging (MRI) will allow mapping molecular information on a high definition anatomical reference and enable the use of prior information on tissue’s optical properties to enhance both resolution and sensitivity. Today many of the fluorescent assays originally developed for studies in cellular systems have been successfully translated for experimental studies in animals. The opportunity of monitoring molecular processes non-invasively in the intact organism is highly attractive from a diagnostic point of view but even more so for the drug developer, who can use the techniques for proof-of-mechanism and proof-of-efficacy studies. This review shall elucidate the current status and potential of fluorescence tomography including recent advances in multimodality imaging approaches for preclinical and clinical drug development. Full article

(This article belongs to the Special Issue Molecular Imaging)

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1040 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of PKD Inhibitors

by Kara M. George, Marie-Céline Frantz, Karla Bravo-Altamirano, Courtney R. LaValle, Manuj Tandon, Stephanie Leimgruber, Elizabeth R. Sharlow, John S. Lazo, Q. Jane Wang and Peter Wipf

Pharmaceutics 2011, 3(2), 186-228; https://doi.org/10.3390/pharmaceutics3020186 - 21 Apr 2011

Cited by 54 | Viewed by 11162

Abstract

Protein kinase D (PKD) belongs to a family of serine/threonine kinases that play an important role in basic cellular processes and are implicated in the pathogenesis of several diseases. Progress in our understanding of the biological functions of PKD has been limited due [...] Read more.

Protein kinase D (PKD) belongs to a family of serine/threonine kinases that play an important role in basic cellular processes and are implicated in the pathogenesis of several diseases. Progress in our understanding of the biological functions of PKD has been limited due to the lack of a PKD-specific inhibitor. The benzoxoloazepinolone CID755673 was recently reported as the first potent and kinase-selective inhibitor for this enzyme. For structure-activity analysis purposes, a series of analogs was prepared and their in vitro inhibitory potency evaluated. Full article

(This article belongs to the Special Issue Drug Discovery Tools)

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189 KiB

Open AccessReview

Nanotechnology and Drug Delivery: An Update in Oncology

by Tait Jones and Nabil Saba

Pharmaceutics 2011, 3(2), 171-185; https://doi.org/10.3390/pharmaceutics3020171 - 14 Apr 2011

Cited by 13 | Viewed by 8427

Abstract

The field of nanotechnology has exploded in recent years with diverse arrays of applications. Cancer therapeutics have recently seen benefit from nanotechnology with the approval of some early nanoscale drug delivery systems. A diversity of novel delivery systems are currently under investigation and [...] Read more.

The field of nanotechnology has exploded in recent years with diverse arrays of applications. Cancer therapeutics have recently seen benefit from nanotechnology with the approval of some early nanoscale drug delivery systems. A diversity of novel delivery systems are currently under investigation and an array of newly developed, customized particles have reached clinical application. Drug delivery systems have traditionally relied on passive targeting via increased vascular permeability of malignant tissue, known as the enhanced permeability and retention effect (EPR). More recently, there has been an increased use of active targeting by incorporating cell specific ligands such as monoclonal antibodies, lectins, and growth factor receptors. This customizable approach has raised the possibility of drug delivery systems capable of multiple, simultaneous functions, including applications in diagnostics, imaging, and therapy which is paving the way to improved early detection methods, more effective therapy, and better survivorship for cancer patients. Full article

(This article belongs to the Special Issue Nanotechnology in Drug Delivery)

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2094 KiB

Open AccessReview

Live Cell in Vitro and in Vivo Imaging Applications: Accelerating Drug Discovery

by Beverley Isherwood, Paul Timpson, Ewan J McGhee, Kurt I Anderson, Marta Canel, Alan Serrels, Valerie G Brunton and Neil O Carragher

Pharmaceutics 2011, 3(2), 141-170; https://doi.org/10.3390/pharmaceutics3020141 - 04 Apr 2011

Cited by 51 | Viewed by 14313

Abstract

Dynamic regulation of specific molecular processes and cellular phenotypes in live cell systems reveal unique insights into cell fate and drug pharmacology that are not gained from traditional fixed endpoint assays. Recent advances in microscopic imaging platform technology combined with the development of [...] Read more.

Dynamic regulation of specific molecular processes and cellular phenotypes in live cell systems reveal unique insights into cell fate and drug pharmacology that are not gained from traditional fixed endpoint assays. Recent advances in microscopic imaging platform technology combined with the development of novel optical biosensors and sophisticated image analysis solutions have increased the scope of live cell imaging applications in drug discovery. We highlight recent literature examples where live cell imaging has uncovered novel insight into biological mechanism or drug mode-of-action. We survey distinct types of optical biosensors and associated analytical methods for monitoring molecular dynamics, in vitro and in vivo. We describe the recent expansion of live cell imaging into automated target validation and drug screening activities through the development of dedicated brightfield and fluorescence kinetic imaging platforms. We provide specific examples of how temporal profiling of phenotypic response signatures using such kinetic imaging platforms can increase the value of in vitro high-content screening. Finally, we offer a prospective view of how further application and development of live cell imaging technology and reagents can accelerate preclinical lead optimization cycles and enhance the in vitro to in vivo translation of drug candidates. Full article

(This article belongs to the Special Issue Drug Discovery Tools)

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401 KiB

Open AccessArticle

Efficient Gene Silencing by Self-Assembled Complexes of siRNA and Symmetrical Fatty Acid Amides of Spermine

by Abdelkader A. Metwally, Charareh Pourzand and Ian S. Blagbrough

Pharmaceutics 2011, 3(2), 125-140; https://doi.org/10.3390/pharmaceutics3020125 - 25 Mar 2011

Cited by 14 | Viewed by 9687

Abstract

Gene silencing by siRNA (synthetic dsRNA of 21-25 nucleotides) is a well established biological tool in gene expression studies and has a promising therapeutic potential for difficult-to-treat diseases. Five fatty acids of various chain length and oxidation state (C12:0, C18:0, C18:1, C18:2, C22:1) [...] Read more.

Gene silencing by siRNA (synthetic dsRNA of 21-25 nucleotides) is a well established biological tool in gene expression studies and has a promising therapeutic potential for difficult-to-treat diseases. Five fatty acids of various chain length and oxidation state (C12:0, C18:0, C18:1, C18:2, C22:1) were conjugated to the naturally occurring polyamine, spermine, and evaluated for siRNA delivery and gene knock-down. siRNA delivery could not be related directly to gene silencing efficiency as N⁴,N⁹-dierucoyl spermine resulted in higher siRNA delivery compared to N⁴,N⁹-dioleoyl spermine. GFP silencing in HeLa cells showed that the unsaturated fatty acid amides are more efficient than saturated fatty acid amides, with N⁴,N⁹-dioleoyl spermine resulting in the most efficient gene silencing in the presence of serum. The alamarBlue cell viability assay showed that fatty acid amides of spermine have good viability (75%–85% compared to control) except N⁴,N⁹-dilauroyl spermine which resulted in low cell viability. These results prove that unsaturated fatty acid amides of spermine are efficient, non-toxic, non-viral vectors for siRNA mediated gene silencing. Full article

(This article belongs to the Special Issue Delivery and Genomics of Large Molecules)

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Pharmaceutics, Volume 3, Issue 2 (June 2011) – 9 articles , Pages 125-337

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