Jeffrey Wang

Treating Type 2 Diabetes Mellitus with Traditional Chinese and Indian Medicinal Herbs

Type II diabetes mellitus (T2DM) is a fast-growing epidemic affecting people globally. Furthermore, multiple complications and comorbidities are associated with T2DM. Lifestyle modifications along with pharmacotherapy and patient education are the mainstay of therapy for patients afflicted with T2DM. Western medications are frequently associated with severe adverse drug reactions and high costs of treatment. Herbal medications have long been used in the treatment and prevention of T2DM in both traditional Chinese medicine (TCM) and traditional Indian medicine (TIM). This review examines in vivo, in vitro, and clinical evidence supporting the use of various herbs used in TCM and TIM. The problems, challenges, and opportunities for the incorporation of herbal frequently used in TCM and TIM into Western therapy are presented and discussed.

Chemoprevention of pancreatic cancer using solid-lipid nanoparticulate delivery of a novel aspirin, curcumin and sulforaphane drug combination regimen

Pancreatic cancer is the fourth largest cause of cancer deaths in the Unites States and the prognosis is grim with <5% survival chances upon diagnosis. The objective of this study was to assess the combined chemopreventive effect of solid lipid nanoparticle (SLN) encapsulated drugs aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN) for the chemoprevention of pancreatic cancer. Experiments were carried out (1) to evaluate the feasibility of encapsulation of these chemopreventive agents within solid lipid systems and (2) to measure the synergistic effects of a combination of ASP with CUR in SLNs mixed with free SFN against cell proliferation and apoptosis in pancreatic cancer cells, MIA PaCa-2 and Panc-1. The SLNs were prepared using a modified solvent evaporation technique and were characterized for particle sizing, encapsulation efficiency and drug release. ASP and CUR SLNs were formulated within the particle size range of 150–250 nm and were found to have an encapsulation efficiency of 85 and 69%, respectively. Sustained release of drugs over a 96 h period from SLNs was observed. The SLNs were stable over a 3-month storage period at room temperature. Cell viability studies demonstrated that combinations of low doses of ASP SLN (25 μM), CUR SLN (2.5 μM) and free SFN (5 μM) significantly reduced cell viability by 43.6 and 48.49% in MIAPaca-2 and Panc-1 cell lines, respectively. Furthermore, increased apoptosis of 61.3 and 60.37% was found in MIA Paca-2 and Panc-1 cell lines, respectively, in comparison to the individual doses administered. Synergistic effects were demonstrated using MTS and apoptosis assays. Thus, this study successfully demonstrated the feasibility of using a solid lipid nanoparticulate system for the first time to deliver this novel combination chemoprevention regimen, providing valuable evidence for the usability of nanotechnology-based drug regimens towards pancreatic cancer chemoprevention.

PEGylated Liposome Encapsulation Increases the Lung Tissue Concentration of Vancomycin

ABSTRACT Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) often cannot be cured by vancomycin treatment. Poor lung tissue and intracellular penetration limits the ability to achieve effective bactericidal levels, particularly in alveolar macrophages, where MRSA can evade phagocytic killing. Compared to standard formulations, liposome encapsulation has been shown to enhance vancomycin intracellular killing of MRSA. In this murine pharmacokinetic and biodistribution study, PEGylated liposomal vancomycin, compared to standard and non-PEGylated formulations, significantly prolonged blood circulation time and increased deposition in lung, liver, and spleen and yet reduced accumulation in kidney tissue. As a result of optimizing antimicrobial targeting of infected lung tissue and limiting renal parenchymal exposure, administration of PEGylated liposomal vancomycin may improve the efficacy of treatment of MRSA pneumonia and reduce the risk of nephrotoxicity.

The molecular mechanism of action of aspirin, curcumin and sulforaphane combinations in the chemoprevention of pancreatic cancer

Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with ~37,000 deaths each year. The present study evaluated the chemopreventive potential of a combination of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) in low doses to human pancreatic cancer cells, MIA PaCa-2 and Panc-1. Results demonstrated that low doses of ASP (1 mM), CUR (10 μM) and SFN (5 μM) (ACS) combination reduced cell viability by ~70% (P<0.001), and also induced cell apoptosis by ~51% (P<0.001) accompanied by activation of caspase-3 and Poly(ADP-ribose) polymerase (PARP) proteins. The NF-κB DNA binding activity was inhibited by ~45% (P<0.01) and ~75% (P<0.001) in MIA PaCa-2 and Panc-1 cells, respectively. Mechanistic studies revealed that ACS promoted increase expression of phospho extracellular signal-regulated kinase 1/2 (P-ERK1/2), c-Jun, p38 MAPK and p53 proteins. Furthermore, the cells pretreated with U0126 (ERK1/2 inhibitor) partially abolished the effect of ACS on cell viability. Data from this study demonstrate that a low-dose ACS combination inhibits cell growth by inducing cell apoptosis, and proposes sustained activation of the ERK1/2 signaling pathway as one of the possible mechanisms.

Reversible Lipidization Prolongs the Pharmacological Effect, Plasma Duration, and Liver Retention of Octreotide

No HeadingPurpose.Octreotide (OCT) was reversibly lipidized to improve the pharmacological effect and to increase the plasma half-life and the liver retention of OCT for greater therapeutic potential in the treatment of liver cancers such as hepatocellular carcinoma.Methods.OCT was chemically modified using reversible aqueous lipidization (REAL) technology. REAL-modified OCT (REAL-OCT) was characterized with high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. A single dose of OCT or REAL-OCT or vehicle only was subcutaneously administered to male Sprague-Dawley rats, and the plasma growth hormone (GH) levels were measured after an intravenous injection of 2.5 μg/kg of growth hormone releasing factor (GRF) to assess the ability of REAL-OCT on GH inhibition. Radio-iodinated Tyr3-OCT (TOC) and REAL-TOC were used for pharmacokinetic studies.Results.At 0.1 mg/kg, REAL-OCT inhibited the GRF-induced GH surge in rats for a greater than 24-h period in comparison to the 6-h period for OCT. The distribution and elimination half-life for 125I-REAL-TOC were 1.4 h and 6.6 h, respectively, which were significantly longer than those of 125I-TOC. Sustained high blood concentrations and reduced in vivo degradation were observed for 125I-REAL-TOC. In addition, 125I-REAL-TOC appeared to be targeted to the liver with persistent high liver retention.Conclusions.REAL-OCT has a significantly enhanced pharmacological effect, and this is most likely due to the favorable changes in the pharmacokinetic parameters upon lipidization. The observed liver targeting effect of REAL-TOC suggests that REAL-OCT might be advantageous over OCT in treating liver cancers.

A Novel Combinatorial Nanotechnology-based Oral Chemopreventive Regimen Demonstrates Significant Suppression of Pancreatic Cancer Neoplastic Lesions

Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still less than 5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low-dose combinations of aspirin, curcumin, and sulforaphane (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. The use of three different doses (low, medium, and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50%, and 68.7% respectively; whereas the modified nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed a notable reduction in cell proliferation, the SLN encapsulated ACS regimens showed significant reduction in cell proliferation at 6.3%, 58.6%, and 72.8% as evidenced by proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with BOP control. These studies provide a proof-of-concept for the use of an oral, low-dose, nanotechnology-based combinatorial regimen for the long-term chemoprevention of pancreatic cancer. Cancer Prev Res; 6(10); 1015–25. ©2013 AACR.

Genetic variations and gene expression of transporters in drug disposition and response

Background: The importance of transporters in drug disposition and response has led to increasing interest in genetic variations and expression differences of their genes. Objective: This review summarizes: i) genetic variations in transporters and associated drug response; and ii) a pharmacogenomic approach to correlate transporter expression and drug response. Methods: Several transporters in ATP-binding cassette family and solute carrier family are discussed. Conclusion: The field of transporter pharmacogenomics is in its early stage. Transporter expression at mRNA levels could be more directly related to their functions and more practical to be assayed in high throughput. Correlating microarray expression of transporters with anticancer drug activity in the NCI-60 panel has provided an approach for identifying drug-transporter relationships and predicting drug response.

Development and stability studies of novel liposomal vancomycin formulations.

A promising strategy to improve the therapeutic efficiency of antimicrobial agents is targeted therapy. Although vancomycin has been considered a gold standard for the therapy of MRSA pneumonia, clinical failure rates have also been reported owing to its slow, time-dependent bactericidal activity, variable lung tissue penetration and poor intracellular penetration into macrophages. Liposomal encapsulation has been established as an alternative for antimicrobial delivery to infected tissue macrophages and offers enhanced pharmacodynamics, pharmacokinetics and decreased toxicity compared to standard preparations. The aim of the present work is to prepare vancomycin in two different liposomal formulations, conventional and PEGylated liposomes using different methods. The prepared formulations were optimized for their particle size, encapsulation efficiency and physical stability. The dehydration-rehydration was found to be the best preparation method. Both the conventional and PEGylated liposomal formulations were successfully formulated with a narrow particle size and size distribution and % encapsulation efficiency of 9 ± 2 and 12 ± 3, respectively. Both the formulations were stable at 4°C for 3 months. These formulations were successfully used to evaluate for their intracellular killing of MRSA and in vivo pharmacokinetic and bio-distribution studies.

Development and validation of a high-performance liquid chromatography method for the simultaneous determination of aspirin and folic acid from nano-particulate systems

Attention has shifted from the treatment of colorectal cancer (CRC) to chemoprevention using aspirin and folic acid as agents capable of preventing the onset of colon cancer. However, no sensitive analytical method exists to simultaneously quantify the two drugs when released from polymer-based nanoparticles. Thus, a rapid, highly sensitive method of high-performance liquid chromatography analysis to simultaneously detect low quantities of aspirin (hydrolyzed to salicylic acid, the active moiety) and folic acid released from biodegradable polylactide-co-glycolide (PLGA) copolymer nanoparticles was developed. Analysis was done on a reversed-phase C(18) column using a photodiode array detector at wavelengths of 233 nm (salicylic acid) and 277 nm (folic acid). The mobile phase consisted of acetonitrile-0.1% trifluoroacetic acid mixture programmed for a 30 min gradient elution analysis. In the range of 0.1-100 microg/mL, the assay showed good linearity for salicylic acid (R(2) = 0.9996) and folic acid (R(2) = 0.9998). The method demonstrated good reproducibility, intra- and inter-day precision and accuracy (99.67, 100.1%) and low values of detection (0.03, 0.01 microg/mL) and quantitation (0.1 and 0.05 microg/mL) for salicylic acid and folic acid, respectively. The suitability of the method was demonstrated by simultaneously determining salicylic acid and folic acid released from PLGA nanoparticles.

Phytochemical Analysis of Medicinal Plants with Kidney Protective Activities

In view of the increasing number of patients undergoing kidney dialysis or transplant every year, a survey of the literature on renal protective medicinal plants was undertaken. Most of them are from traditional Chinese medicine (TCM). Although many of the medicinal herbs reported have not been investigated in terms of active chemical ingredients, some do have compounds well characterized. They fall into a wide range of structures. Several groups of compounds with well established activities are discussed. These include: antioxidant phenolic compounds like tannins, flavonoids, isoflavonoids, unsaturated organic acids and lignans; circulation enhancing compounds like saponins, and basic alkaloids with multiple targets (G-protein coupled receptors). Also presented are proinflammatory and antiinflammatory fatty acids like linoleic (n-6) and α-linolenic (n-3) acids, respectively. Attention is also drawn to the plants containing nephrotoxic aristolochic acid. Different directions of future research are also presented. We hope that this review may provide some leads for new drug discovery and development, and more rational application of TCM.