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1.  Optimum Topical Delivery of Adrenergic Agonists to Oral Mucosa Vasculature 
Pharmaceutical research  2014;32(2):492-499.
Purpose
Identify an orotopical vehicle to deliver an α-adrenergic vasoconstrictor to submucosal vasculature that is readily palatable to cancer/bone marrow transplant patients that suppresses chemo-radiotherapy-associated oral mucositis.
Methods
A [3H] norepinephrine ligand binding assay was developed to quantify receptor binding in hamster oral mucosa. Vehicle components (alcohols, polyols, cellulose, PVP) were tested versus [3H] norepinephrine binding. Vehicle refinement was also done to mask phenylephrine bitter taste and achieve human subject acceptance. The optimized vehicle was tested with α-adrenergic active agents to suppress radiation-induced oral mucositis in mice.
Results
The ligand binding assay quantified dose- and time-dependent, saturable binding of [3H] norepinephrine. An ethanol:glycerol:propylene glycol:water (6:6:8:80) vehicle provided the best delivery and binding. Further vehicle modification (flavoring and sucralose) yielded a vehicle with excellent taste scores in humans. Addition of phenylephrine, norepinephrine or epinephrine to the optimized vehicle and painting into mouse mouths 20 min before 19 Gy irradiation conferred significant suppression of the weight loss (P < 0.001) observed in mice who received oral vehicle.
Conclusion
We identified a highly efficient vehicle for the topical delivery of phenylephrine to the oral mucosa of both hamster and human subjects. This will enable its testing to suppress oral mucositis in an upcoming human clinical trial.
doi:10.1007/s11095-014-1477-1
PMCID: PMC4324606  PMID: 25079392
alpha adrenergic vasoconstrictor; epinephrine; norepinephrine; phenylephrine; topical formulation
2.  [No title available] 
PMCID: PMC3930621  PMID: 23959854
3.  [No title available] 
PMCID: PMC3930629  PMID: 23959852
4.  [No title available] 
PMCID: PMC3946900  PMID: 24019023
5.  [No title available] 
PMCID: PMC3946921  PMID: 23949304
6.  [No title available] 
PMCID: PMC3946937  PMID: 24132686
7.  [No title available] 
PMCID: PMC4289905  PMID: 22274556
8.  Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells 
Pharmaceutical research  2013;31(1):10.1007/s11095-013-1134-0.
Purpose
Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells.
Methods
The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model.
Results
Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment.
Conclusion
PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer.
doi:10.1007/s11095-013-1134-0
PMCID: PMC3864614  PMID: 23884568
phosphodiesterase type 5 (PDE5) inhibitor; doxorubicin; trastuzumab; endocytosis; lung cancer
9.  Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin 
Pharmaceutical research  2013;31(1):10.1007/s11095-013-1147-8.
Purpose
The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone.
Methods
Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship.
Results
The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement.
Conclusion
The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.
doi:10.1007/s11095-013-1147-8
PMCID: PMC3870048  PMID: 23943543
codrugs; drug delivery; microneedle; stability; transdermal
10.  Dissolvable Microneedle Arrays for Intradermal Delivery of Biologics: Fabrication and Application 
Pharmaceutical research  2013;31(1):117-135.
Purpose
Design and evaluate a new micro-machining based approach for fabricating dissolvable microneedle arrays (MNAs) with diverse geometries and from different materials for dry delivery to skin microenvironments. The aims are to describe the new fabrication method, to evaluate geometric and material capability as well as reproducibility of the method, and to demonstrate the effectiveness of fabricated MNAs in delivering bioactive molecules.
Methods
Precise master molds were created using micromilling. Micromolding was used to create elastomer production molds from master molds. The dissolvable MNAs were then fabricated using the spin-casting method. Fabricated MNAs with different geometries were evaluated for reproducibility. MNAs from different materials were fabricated to show material capability. MNAs with embedded bioactive components were tested for functionality on human and mice skin.
Results
MNAs with different geometries and from carboxymethyl cellulose, polyvinyl pyrrolidone and maltodextrin were created reproducibly using our method. MNAs successfully pierce the skin, precisely deliver their bioactive cargo to skin and induce specific immunity in mice.
Conclusions
We demonstrated that the new fabrication approach enables creating dissolvable MNAs with diverse geometries and from different materials reproducibly. We also demonstrated the application of MNAs for precise and specific delivery of biomolecules to skin microenvironments in vitro and in vivo.
doi:10.1007/s11095-013-1137-x
PMCID: PMC3898465  PMID: 23904139
cutaneous drug delivery; dissolvable microneedle arrays; immunization; micro-fabrication; micromilling
11.  Effect of ingested lipids on drug dissolution and release with concurrent digestion: a modeling approach 
Pharmaceutical research  2013;30(12):3131-3144.
Purpose
To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen.
Methods
Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model.
Results
Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion were observed and predicted by the developed model. 90 minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion.
Conclusion
A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.
doi:10.1007/s11095-013-1238-6
PMCID: PMC4281523  PMID: 24234918
12.  Acidic Microclimate pH Distribution in PLGA Microspheres Monitored by Confocal Laser Scanning Microscopy 
Pharmaceutical research  2008;25(9):2041-2052.
The microclimate pH (μpH) distribution inside poly(lactic-co-glycolic acid) (PLGA) microspheres was monitored quantitatively over an acidic range as a function of several formulation variables. A ratiometric method by confocal laser scanning microscopy with Lysosensor yellow/blue® dextran was adapted from those previously reported, and μpH distribution kinetics inside PLGA microspheres was examined during incubation under physiologic conditions for 4 weeks. The effects of polymer molecular weight (MW) and lactic/glycolic acid ratio, microspheres size and preparation method, and polymer blending with poly(ethylene glycol) (PEG) were evaluated. The μpH kinetics was accurately sensed by the dye over a broadly acidic range (2.8 < μpH < 5.8) to compliment our previously reported method detecting neutral μpH. μpH was found be more acidic and variable inside PLGA with lower MW and lactic/glycolic acid ratio during incubation for 4 weeks. A more acidic environment was found in larger size microspheres with lower MW polymers, but microsphere size effects for lactic-rich polymers were not significant during 4 weeks. Importantly, PLGA 50/50 microspheres prepared by the oil-in-oil emulsion method were less acidic than those microspheres prepared by double emulsion, and blending PLGA 50/50 with 20% PEG increased μpH significantly with most aqueous pores exhibiting a pH > 5 throughout the incubation period. Hence, coupling this method with that previously developed with a neutral pH-sensitive dye, SNARF-dextran (5.8 – 8.0), should provide us in the future with microclimate pH mapping over the entire useful pH range (2.8–8.0) for optimization of PLGA delivery of pH-sensitive bioactive substances.
doi:10.1007/s11095-008-9594-3
PMCID: PMC4269251  PMID: 18622692
Microclimate pH; Confocal laser scanning microscopy; Poly(lactic-co-glycolic acid); Microspheres; pH distribution; Poly(ethylene glycol)
13.  Inhibition of peptide acylation in PLGA microspheres with water-soluble divalent cationic salts 
Pharmaceutical research  2009;26(8):1986-1994.
Purpose
To test the potential of water-soluble divalent cationic salts to inhibit acylation of octreotide encapsulated in poly(D,L-lactic-co-glycolic acid)-star (PLGA) microspheres.
Methods
The divalent cationic salts, calcium chloride and manganese chloride, previously shown to disrupt peptide sorption, were introduced in PLGA microspheres prepared by the double emulsion-solvent evaporation method. Peptide stability was monitored by reversed-phase high performance liquid chromatography (RP-HPLC) and identified by liquid chromatography coupled with mass spectrometry (LC-MS) during microsphere degradation under physiological conditions for four weeks. Microsphere morphology and salt content were examined by scanning electron microscopy (SEM) and inductively coupled plasma-optical emission spectroscopy (ICP-OES), respectively.
Results
Addition of divalent cationic salts solely to the organic phase provided marginal acylation inhibition. However, upon addition of the salt inhibitors to both the primary emulsion and the outer water phase resulted in improved drug and salt encapsulation efficiency as well as significantly decreased salt leaching and octreotide acylation. After 28 days, the extent of acylation inhibition afforded by divalent cations was > 58% relative to 13 % for the NaCl control group.
Conclusions
Divalent cationic salts are suitable class of stabilizers of peptide acylation in PLGA microspheres and this study provides an important formulation approach to maximize stabilizer potency.
doi:10.1007/s11095-009-9914-2
PMCID: PMC4260456  PMID: 19533307
Peptide stability; Acylation; Sorption; Divalent cations; Controlled release
14.  Demonstration of ATP dependent, transcellular transport of lipid across the lymphatic endothelium using an in vitro model of the lacteal 
Pharmaceutical research  2013;30(12):10.1007/s11095-013-1218-x.
Purpose
The lymphatic system plays crucial roles in tissue fluid balance, trafficking of immune cells, and the uptake of dietary lipid from the intestine. Given these roles there has been an interest in targeting lymphatics through oral lipid-based formulations or intradermal delivery of drug carrier systems. However the mechanisms regulating lipid uptake by lymphatics remain unknown. Thus we sought to modify a previously developed in vitro model to investigate the role of ATP in lipid uptake into the lymphatics.
Methods
Lymphatic endothelial cells were cultured on a transwell membrane and the effective permeability to free fatty acid and Caco-2 cell-secreted lipid was calculated in the presence or absence of the ATP-inhibitor sodium azide. Results: ATP inhibition reduced Caco-2 cell-secreted lipid transport, but not dextran transport. FFA transport was ATP-dependent primarily during early periods of ATP-inhibition, while Caco-2 cell-secreted lipid transport was lowered at all time points studied. Furthermore, the transcellular component of transport was highly ATP-dependent, a mechanism not observed in fibroblasts, suggesting these mechanisms are unique to lymphatics. Total transport of Caco-2 cell-secreted lipid was dose-dependently reduced by ATP inhibition, and transcellular lipoprotein transport was completely attenuated.
Conclusion
The transport of lipid across the lymphatic endothelium as demonstrated with this in vitro model occurs in part by an ATP-dependent, transcellular route independent of passive permeability. It remains to be determined the extent that this mechanism exists in vivo and future work should be directed in this area.
doi:10.1007/s11095-013-1218-x
PMCID: PMC3849718  PMID: 24254195
15.  Targeted Delivery of PSC-RANTES for HIV-1 Prevention using Biodegradable Nanoparticles 
Pharmaceutical research  2008;26(3):502-511.
Purpose
Nanoparticles formulated from the biodegradable co-polymer poly(lactic-co-glycolic acid) (PLGA), were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting for PSC-RANTES anti-HIV-1 activity.
Materials and Methods
PSC-RANTES nanoparticles formulated via a double emulsion process and characterized in both in vitro and ex vivo systems to determine PSC-RANTES release rate, nanoparticle tissue permeation, and anti-HIV bioactivity.
Results
Spherical, monodisperse (PDI = 0.098 ± 0.054) PSC-RANTES nanoparticles (d = 256.58 ± 19.57 nm) with an encapsulation efficiency of 82.23 ± 8.35% were manufactured. In vitro release studies demonstrated a controlled release profile of PSC-RANTES (71.48 ± 5.25% release). PSC-RANTES nanoparticle maintained comparable anti-HIV activity with unformulated PSC-RANTES in a HeLa cell-based system with an IC50 of approximately 1pM. In an ex vivo cervical tissue model, PSC-RANTES nanoparticles displayed a fivefold increase in tissue uptake, enhanced tissue permeation, and significant localization at the basal layers of the epithelium over unformulated PSC-RANTES.
Conclusions
These results indicate that PSC-RANTES can readily be encapsulated into a PLGA nanoparticle drug delivery system, retain its anti-HIV-1 activity, and deliver PSC-RANTES to the target tissue. This is crucial for the success of this drug candidate as a topical microbicide product.
doi:10.1007/s11095-008-9765-2
PMCID: PMC4243299  PMID: 19002569
drug delivery; HIV-1 prevention; microbicide; nanoparticles; PSC-RANTES
16.  Effect of Caloric Restriction and AMPK Activation on Hepatic Nuclear Receptor, Biotransformation Enzyme, and Transporter Expression in Lean and Obese Mice 
Pharmaceutical research  2013;30(9):2232-2247.
Purpose
Fatty liver alters liver transporter expression. Caloric restriction (CR), the recommended therapy to reverse fatty liver, increases Sirtuin1 deacetylase activity in liver. This study evaluated whether CR and CR mimetics reversed obesity-induced transporter expression in liver and hepatocytes.
Methods
mRNA and protein expression was determined in adult lean (lean) and leptin-deficient obese (OB) mice fed ad libitum or placed on 40% (kCal) reduced diet. Hepatocytes were isolated from lean and OB mice, treated with AMP Kinase activators, and gene expression was determined.
Results
CR decreased Oatp1a1, Oatp1b2, and Abcb11 mRNA expression in lean, but not OB mice. CR increased Abcc2 mRNA OB livers, whereas protein expression increased in both genotypes. CR increased Abcc3 protein expression increased in OB livers. CR did not alter Abcc1, 4 and 5 mRNA expression in lean mice but decreased expression in livers of OB mice. CR increased Abcc4 protein in lean, but not OB mice.
Conclusions
CR restriction reversed the expression of some, but not all transporters in livers of OB mice. Overall, these data indicate a potential for CR to restore some hepatic transporter changes in OB mice, but suggest a functional leptin axis is needed for reversal of expression for some transporters.
doi:10.1007/s11095-013-1140-2
PMCID: PMC4225720  PMID: 23949303
gene expression; liver; nuclear receptor; steatosis; transport
17.  In Vivo Absorption and Disposition of Cefadroxil after Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice 
Pharmaceutical research  2013;30(11):10.1007/s11095-013-1168-3.
Purpose
To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug.
Methods
The absorption and disposition kinetics of [3H]cefadroxil was determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil was also determined in both genotypes after 44.5 nmol/g intravenous bolus doses.
Results
PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil was not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations.
Conclusions
The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs.
doi:10.1007/s11095-013-1168-3
PMCID: PMC3844101  PMID: 23959853
cefadroxil; oral absorption; tissue distribution; knockout mice; PepT1
18.  Rutin Suppresses Palmitic Acids-triggered Inflammation in Macrophages and Blocks High Fat Diet-induced Obesity and Fatty Liver in Mice 
Pharmaceutical research  2013;30(11):2940-2950.
Purpose
To elucidate the mechanism of rutin in blocking macrophage-mediated inflammation and high fat diet-induced obesity and fatty liver.
Methods
Both in vitro and in vivo approaches were taken in evaluating the effects of rutin on palmitic acids-triggered inflammation in cultured macrophages, and on weight gain and development of fatty liver of mice fed a high fat diet.
Results
Palmitic acids increase mRNA levels of pro-inflammatory cytokines, and elevate the production of TNFα in cultured macrophages. Pre-exposure of rutin to cells greatly suppressed these elevations. The suppressed inflammation by rutin was correlated with a decrease in transcription of genes responsible for ER stress and production of reactive oxygen species. In vivo, rutin protects mice from high fat diet-induced obesity, fatty liver and insulin resistance. The protective effects were associated with lack of hypertrophy and crown-like structures in the white adipose tissue, decreased mRNA levels of marker genes for macrophages including F4/80, Cd11c and Cd68, and repressed transcription of genes involved in chronic inflammation such as Mcp1 and Tnfα in white adipose tissue. In addition, rutin increases the expression of genes responsible for energy expenditure in brown adipose tissue including Pgc1α and Dio2. Furthermore, rutin suppresses transcription of Srebp1c and Cd36 in the liver, leading to a blockade of fatty liver development.
Conclusion
These results suggest that supplementation of rutin is a promising strategy for blocking macrophage-mediated inflammation and inflammation-induced obesity and its associated complications.
doi:10.1007/s11095-013-1125-1
PMCID: PMC3800247  PMID: 23783345
rutin; anti-oxydant; chronic inflammation; high fat diet; obesity; fatty liver; insulin resistance
19.  Omeprazole and PGC-formulated heparin binding epidermal growth factor normalizes fasting blood glucose and suppresses insulitis in multiple low dose streptozotocin diabetes model 
Pharmaceutical research  2013;30(11):2843-2854.
Purpose
Our objective was to develop novel nanocarriers (protected graft copolymer, PGC) that improve the stability of heparin binding EGF (HBEGF) and gastrin and then to use PGC-formulated HBEGF (PGC-HBEGF) and Omeprazole (+/− PGC-gastrin) for normalizing fasting blood glucose (FBG) and improving islet function in diabetic mice.
Method
HBEGF, PGC-HBEGF, Omeprazole, Omeprazole+PGC-HBEGF, Omeprazole+PGC-gastrin+PGC-HBEGF and epidermal growth factor (EGF)+gastrin were tested in multiple low dose streptozotocin diabetic mice.
Results
Omeprazole+PGC-HBEGF normalized FBG and is better than EGF+gastrin at improving islet function and decreasing insulitis. Groups treated with Omeprazole, Omeprazole+PGC-HBEGF, or EGF+gastrin have significantly improved islet function versus saline control. All animals that received PGC-HBEGF had significantly reduced islet insulitis versus saline control. Non-FBG was lower for Omeprazole+PGC-gastrin+PGC-HBEGF but Omeprazole+PGC-HBEGF alone showed better FBG and glucose tolerance.
Conclusions
Omeprazole+PGC-HBEGF provides a sustained exposure to both EGFRA and gastrin, improves islet function, and decreases insulitis in multiple low dose streptozotocin diabetic mice. Although HBEGF or EGF elevates non-FBG, it facilitates a reduction of insulitis and, in the presence of Omeprazole, provides normalization of FBG at the end of treatment. The study demonstrates Omeprazole and PGC-HBEGF is a viable treatment for diabetes.
doi:10.1007/s11095-013-1112-6
PMCID: PMC3800254  PMID: 23793991
type 1 diabetes; growth factors; nanocarrier; insulitis; islet function
20.  The Use of Condensational Growth Methods for Efficient Drug Delivery to the Lungs during Noninvasive Ventilation High Flow Therapy 
Pharmaceutical research  2013;30(11):2917-2930.
Purpose
The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques.
Methods
An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations.
Results
Significant improvement in the lung dose (3–4x increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5μm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results.
Conclusions
These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally-administered drugs to the lungs.
doi:10.1007/s11095-013-1123-3
PMCID: PMC3800269  PMID: 23801087
Combination drug-excipient particles; enhanced condensational growth; excipient enhanced growth; hygroscopic growth; noninvasive aerosol therapy; nose-to-lung aerosol delivery
21.  Influence of Gallate Esterification on the Activity of Procyanidin B2 in Androgen-dependent Human Prostate Carcinoma LNCaP Cells 
Pharmaceutical research  2010;27(4):619-627.
Purpose
Present study assessed the influence of gallate esterification on the anti-cancer activity of procyanidin B2 (B2) in androgen-dependent human prostate carcinoma LNCaP cells employing B2-3,3'-di-O-gallate (B2-G2), two mono-gallate esters B2-3-O-gallate (B2-3G) and B2-3’-O-gallate (B2-3’G) and the parent compound B2, all isolated from grape seed extract (GSE).
Materials and Methods
Study compounds were isolated from GSE by several chromatographic steps and structures determined by a combination of enzymatic hydrolysis, mass spectrometry and comparisons with standards. Cells, treated with these compounds, were assessed for viability and apoptosis and examined by western blotting.
Results
Gallate esters B2-G2, B2-3G and B2-3’G significantly decreased LNCaP cell viability; however, B2 and gallic acid were ineffective. Furthermore, only B2-G2 also significantly decreased cell growth. Decreases in cell viability were largely due to apoptosis induction with B2-G2 and B2-3’G exhibiting comparable effects, whereas B2-3G was less effective. In mechanistic studies, B2-G2 and B2-3’G treatments caused caspases-9 and –3 and PARP cleavage, and down-regulated Bcl-2, Bcl-Xl and androgen receptor levels.
Conclusion
Together, our findings demonstrate anti-PCA efficacy of B2-G2 and suggest that a gallate ester moiety at 3’ position of procyanidin B2 contributes more extensively toward the biological activity of the di-gallate ester than esterification of position 3.
doi:10.1007/s11095-009-0037-6
PMCID: PMC4208699  PMID: 20162340
Prostate cancer; chemoprevention; grape seed extract; procyanidins; apoptosis
22.  Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats 
Pharmaceutical research  2007;25(4):769-780.
Purpose
This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis.
Materials and methods
Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG).
Results
MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40–50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60–70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols.
Conclusions
Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future.
doi:10.1007/s11095-007-9371-8
PMCID: PMC4196440  PMID: 17674160
cholesterol; corticosteroids; glucocorticoid receptors; LDL receptors; lipids; pharmacodynamics
23.  Magnetic Nanoparticles for Tumor Imaging and Therapy: A So-called Theranostic System 
Pharmaceutical research  2013;30(10):2445-2458.
In this review, we discussed the establishment of a so-called “theranostic“ system by instituting the basic principles including the use of: [1] magnetic iron oxide nanoparticles (MION)-based drug carrier; [2] intra-arterial (I.A.) magnetic targeting; [3] macromolecular drugs with unmatched therapeutic potency and a repetitive reaction mechanism; [4] cell-penetrating peptide-mediated cellular drug uptake; and [5] heparin/protamine-regulated prodrug protection and tumor-specific drug re-activation into one single drug delivery system to overcome all possible obstacles, thereby achieving a potentially non-invasive, magnetic resonance imaging-guided, clinically enabled yet minimally toxic brain tumor drug therapy. By applying a topography-optimized I.A. magnetic targeting to dodge rapid organ clearance of the carrier during its first passage into the circulation, tumor capture of MION was enriched by >350 folds over that by conventional passive enhanced permeability and retention targeting. By adopting the prodrug strategy, we observed by far the first experimental success in a rat model of delivering micro-gram quantity of the large β-galactosidase model protein selectively into a brain tumor but not to the ipsi- or contra-lateral normal brain regions. With the therapeutic regimens of most toxin/siRNA drugs to fully (>99.9%) eradicate a tumor being in the nano-molar range, the prospects of reaching this threshold become practically accomplishable.
doi:10.1007/s11095-013-0982-y
PMCID: PMC4171953  PMID: 23344909
magnetic nanoparticles; brain tumor/cancer; tumor imaging and therapy; theranostic system; cell-penetrating peptide
24.  Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability 
Pharmaceutical research  2007;24(6):1088-1097.
Purpose
To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness.
Materials and Methods
Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five - way crossover, placebo - controlled study. Measurements included plasma drug and Cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm.
Results
The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in Cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC50) were larger between subjects (73–118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC50 for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r2 = 0.928).
Conclusions
The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics.
doi:10.1007/s11095-006-9232-x
PMCID: PMC4181339  PMID: 17385022
corticosteroids; mathematical modeling; pharmacodynamics; pharmacokinetics
25.  Application of Scaling Factors in Simultaneous Modeling of Microarray Data from Diverse Chips 
Pharmaceutical research  2007;24(4):643-649.
Purpose
Microarrays have been utilized in many biological, physiological and pharmacological studies as a high-throughput genomic technique. Several generations of Affymetrix GeneChip® microarrays are widely used in gene expression studies. However, differences in intensities of signals for different probe sets that represent the same gene on various types of Affymetrix chips make comparison of datasets complicated.
Materials and Methods
A power coefficient scaling factor was applied in the pharmacokinetic/ pharmacodynamic (PK/PD) modeling to account for differences in probe set sensitivities (i.e., signal intensities). Microarray data from muscle and liver following methylprednisolone 50 mg/kg i.v. bolus and 0.3 mg/kg/h infusion regimens were taken as an exemplar.
Results
The scaling factor applied to the pharmacodynamic output function was used to solve the problem of intensity differences between probe sets. This approach yielded consistent pharmacodynamic parameters for the applied models.
Conclusions
Modeling of pharmacodynamic/pharmacogenomic (PD/PG) data from diverse chips should be performed with caution due to differential probe set intensities. In such circumstances, a power scaling factor can be applied in the modeling.
doi:10.1007/s11095-006-9215-y
PMCID: PMC4181592  PMID: 17318415
bioinformatics; computational biology; pharmacodynamics; pharmacogenomics; pharmacokinetics

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