A Dicarboxylic Fatty Acid Derivative of Paclitaxel for Albumin-Assisted Drug Delivery

Hackett, Michael; Shyamsunder, Joolakanti,; Hartranft, Megan E.; Guley, Patrick C.; Cho, Moo J.

doi:10.1002/jps.23213

Cited by 10 publications

(9 citation statements)

References 44 publications

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“…For example, when using a cyclodextrin as a drug-delivery tool similar to other antibiotics (Cefotiam and Itraconazole) [37] or using serum albumin as a drug carrier. [38] However, we were at- Table 1. Disc diffusion inhibition zone diameters (mm) for compound 10 (10 mg mL À1 ).…”

Section: Resultsmentioning

confidence: 99%

“…36 Several techniques of combating the serum albumin binding through drug formulation were considered. For example, when using a cyclodextrin as a drug‐delivery tool similar to other antibiotics (Cefotiam and Itraconazole)37 or using serum albumin as a drug carrier 38. However, we were attracted to structural modification because of the ease of synthesis of our lead compound 10 .…”

Section: Resultsmentioning

confidence: 99%

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Inspiration from Old Dyes: Tris(stilbene) Compounds as Potent Gram‐Positive Antibacterial Agents

Boulos

Man

Lengkeek

et al. 2013

Chemistry A European J

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Herein we describe the preparation and structure-activity relationship studies on range of stilbene based compounds and their antibacterial activity. Two related compounds, each bearing carboxylic acid moieties, exhibit good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12-0.25 μg mL(-1) and against Staphylococcus spp. with MICs ranging from 2-4 μg mL(-1). The derivative 17 showed increased activity with MICs of 0.06-0.25 μg mL(-1) against M. catarrhalis and 0.12-1 against Staphylococcus spp. This level of activity is similar to that reported for S. aureus for antibiotics, such as vancomycin, with MICs of ≤2.0 μg mL(-1) and clindamycin with MICs of ≤0.5 μg mL(-1). As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of tris(stilbene) compounds as antibacterial agents providing suitable properties for further development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Inspiration from Old Dyes: Tris(stilbene) Compounds as Potent Gram‐Positive Antibacterial Agents

Boulos

Man

Lengkeek

et al. 2013

Chemistry A European J

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“…Especially, oral PTX delivery would enable chronic treatment regimens resulting in sustained therapeutic concentrations and optimal antitumor activity. Unfortunately, aqueous solubility of PTX is less than 10 mg/mL (with reports ranging from 0.1 to 510 mg/mL) and lack of functional groups in its chemical structure precluded any possible salt formation to improve its solubility 7 . Besides, the oral bioavailability (BA) of PTX is very low ($2%) due to its P-glycoprotein (P-gp) mediated efflux across the mucosal cells of the gastrointestinal tract 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Drug Dev Ind Pharm, Early Online:[1][2][3][4][5][6][7][8][9][10][11][12][13] Drug Dev Ind Pharm Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 03/24/15For personal use only.…”

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confidence: 99%

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

Shanmugam

Sohn

et al. 2015

Drug Development and Industrial Pharmacy

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The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20 min. Finally, the PK profile of SDG-T and a reference formulation Oraxol™ (oral solution formulation used in Phase I clinical study) at a dose of 60 mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10 mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol™ solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol™ solution was 132.25% at a dose of 60 mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10-150 ng/mL for a period of 24 h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.

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“…154 Capitalizing on this inevitable interaction, however, the coupling of medications to FA-HSA binding has resulted in improvements to their stability in the body. 155,156 Figure 1-2 A crystal structure of HSA highlighting its fatty acid, heme, and major drug binding sites. Binding sites were elucidated by the analysis of HSA-ligand and/or fatty acid complexes.…”

Section: Human Serum Albumin (Hsa)mentioning

confidence: 99%

Hydroxylated and sulfated metabolites of lower chlorinated PCBs bind with high affinity to human serum albumin and exhibit selective toxicity to neuronal cells

Rodríguez¹

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Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants that have been associated with a myriad of negative human health effects. These man-made compounds were used throughout most of the 20 th century and although their intentional production has since been banned and their use limited to closed systems, their prevalence in the environment remains a factor in disease states for exposed populations. The worldwide levels of PCBs has been declining, however, there is evidence for renewed sources of these compounds. The presence of PCBs have been verified as unintentional byproducts in paints and pigments, the decomposition of PCB waste, or the recycling or disposal attempts of PCB-laden materials. While exposure to the higher chlorinated congeners (˃4 chlorine atoms, HC-PCBs) is often attributed to the consumption of contaminated water or fatty animal meat, a significant route of exposure to airborne lower chlorinated congeners (≤4 chlorine atoms, LC-PCBs) is through inhalation. These semi-volatile compounds have been detected in high quantities in both indoor and outdoor air in urban and rural communities, and their presence is pronounced in older buildings (e.g., homes and schools). When compared to HC-PCBs, LC-PCBs are more highly susceptible to metabolic transformations, and recently their sulfated metabolites have gained much interest. Although the sulfation of xenobiotics often is considered a route for their removal from the body, a previous study of Sprague-Dawley rats treated with 4-chlorobiphenyl (PCB 3) resulted in the substantial formation of sulfated metabolites (i.e., hydroxylation followed by sulfation of the LC-PCB). This metabolic route accounted for more than half of the treatment dose. Furthermore, LC-PCB sulfates have been shown to bind to the human serum protein, transthyretin, in vitro. Of the health effects associated with PCB exposure, neurotoxicity has been well established through various laboratory and epidemiological studies. It is proposed that the dopaminergic system lies at the core of the observed cognitive, motor, and intellectual vii dysfunction observed in exposed populations, especially in children exposed perinatally. Interestingly, PCB exposure has been linked to Parkinson's disease (PD) etiology, which is marked by a substantial loss of dopaminergic neurons. This thesis describes studies on the binding of selected LC-PCBs and their hydroxylated and sulfated metabolites to human serum albumin (HSA), the most abundant protein in human serum. The displacement of fluorescent probes, selective for the two major drug binding sites of HSA, indicated that LC-PCB sulfates generally bound to HSA with such affinity that is equal to or greater than that for the LC-PCBs or OH-LC-PCBs This work also included a study of the selective toxicity of these compounds to dopaminergic neuronal cells. The selective toxicity of these compounds was studied in a series of immortalized cell lines (i.e., two neuronal cell lines: the rat midbrain-derived N27 cell line, the human neuro...

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A Dicarboxylic Fatty Acid Derivative of Paclitaxel for Albumin-Assisted Drug Delivery

Cited by 10 publications

References 44 publications

Inspiration from Old Dyes: Tris(stilbene) Compounds as Potent Gram‐Positive Antibacterial Agents

Inspiration from Old Dyes: Tris(stilbene) Compounds as Potent Gram‐Positive Antibacterial Agents

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

Hydroxylated and sulfated metabolites of lower chlorinated PCBs bind with high affinity to human serum albumin and exhibit selective toxicity to neuronal cells

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