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1.  Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention 
Pomegranate polyphenols are potent antioxidants and chemopreventive agents but have low bioavailability and a short half-life. For example, punicalagin (PU), the major polyphenol in pomegranates, is not absorbed in its intact form but is hydrolyzed to ellagic acid (EA) moieties and rapidly metabolized into short-lived metabolites of EA. We hypothesized that encapsulation of pomegranate polyphenols into biodegradable sustained release nanoparticles (NPs) may circumvent these limitations. We describe here the development, characterization, and bioactivity assessment of novel formulations of poly(D,L-lactic-co-glycolic acid)–poly(ethylene glycol) (PLGA–PEG) NPs loaded with pomegranate extract (PE) or individual polyphenols such as PU or EA. Monodispersed, spherical 150–200 nm average diameter NPs were prepared by the double emulsion–solvent evaporation method. Uptake of Alexa Fluor-488-labeled NPs was evaluated in MCF-7 breast cancer cells over a 24-hour time course. Confocal fluorescent microscopy revealed that PLGA–PEG NPs were efficiently taken up, and the uptake reached the maximum at 24 hours. In addition, we examined the antiproliferative effects of PE-, PU-, and/or EA-loaded NPs in MCF-7 and Hs578T breast cancer cells. We found that PE, PU, and EA nanoprototypes had a 2- to 12-fold enhanced effect on cell growth inhibition compared to their free counterparts, while void NPs did not affect cell growth. PU-NPs were the most potent nanoprototype of pomegranates. Thus, PU may be the polyphenol of choice for further chemoprevention studies with pomegranate nanoprototypes. These data demonstrate that nanotechnology-enabled delivery of pomegranate polyphenols enhances their anticancer effects in breast cancer cells. Thus, pomegranate polyphenols are promising agents for nanochemoprevention of breast cancer.
PMCID: PMC4296962  PMID: 25624761
PLGA–PEG nanoparticles; pomegranate extract; punicalagin; ellagic acid; MCF-7 cells; Hs578T cells
2.  Green tea extract therapy diminishes hepatic fibrosis mediated by dual exposure to carbon tetrachloride and ethanol: A histopathological study 
The aim of the present study was to investigate the hepatoprotective effect of green tea extract (GTE) against the hepatic fibrosis induced by carbon tetrachloride (CCl4), ethanol, and dual exposure to CCl4 plus ethanol in rats. In particular, an investigation of the three-dimensional architecture was conducted using scanning electron microscopy. Various techniques revealed that hepatic fibrosis with intermingled fibers was located between cells in the CCl4, ethanol and combined CCl4 plus ethanol groups. The hepatic fibrosis differed among the ethanol, CCl4 and CCl4 plus ethanol groups in terms of the type, thickness and distribution of fibers. The fibrotic lesions virtually disappeared in all the groups after 25 days of treatment with GTE, returning the architecture of the liver tissue to its normal status. The rats were also found to regain normal body weight and fur color, which had earlier been discolored due to weight loss. The autopsy results also showed that the animal livers returned to the normal shape and color. GTE demonstrated the same clear action in attenuating the hepatofibrosis for all three inducing treatments, by impairing collagen fibers, eliminating lipid peroxidation and returning the liver architecture to normal. GTE presents a safe therapeutic strategy for hepatic fibrosis.
PMCID: PMC4316931  PMID: 25667629
green tea extract; alanine aminotransferase; aspartate aminotransferase; extracellular matrix; carbon tetrachloride plus ethanol; dual exposure; scanning electron microscopy; Masson’s trichrome stain
3.  Tetraiodothyroacetic acid-conjugated PLGA nanoparticles: a nanomedicine approach to treat drug-resistant breast cancer 
Nanomedicine (London, England)  2013;8(12):10.2217/nnm.12.200.
The aim was to evaluate tetraiodothyroacetic acid (tetrac), a thyroid hormone analog of l-thyroxin, conjugated to poly(lactic-co-glycolic acid) nanoparticles (T-PLGA-NPs) both in vitro and in vivo for the treatment of drug-resistant breast cancer.
Materials & methods
The uptake of tetrac and T-PLGA-NPs in doxorubicin-resistant MCF7 (MCF7-Dx) cells was evaluated using confocal microscopy. Cell proliferation assays and a chick chorioallantoic membrane model of FGF2-induced angiogenesis were used to evaluate the anticancer effects of T-PLGA-NPs. In vivo efficacy was examined in a MCF7-Dx orthotopic tumor BALBc nude mouse model.
T-PLGA-NPs were restricted from entering into the cell nucleus, and T-PLGA-NPs inhibited angiogenesis by 100% compared with 60% by free tetrac. T-PLGA-NPs enhanced inhibition of tumor-cell proliferation at a low-dose equivalent of free tetrac. In vivo treatment with either tetrac or T-PLGA-NPs resulted in a three- to five-fold inhibition of tumor weight.
T-PLGA-NPs have high potential as anticancer agents, with possible applications in the treatment of drug-resistant cancer.
PMCID: PMC3825799  PMID: 23448245
angiogenesis; breast cancer; chick chorioallantoic membrane; MCF7 breast cancer cell; nanoparticle; tetrac; thyroid hormone
4.  Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis 
OncoTargets and therapy  2014;7:1619-1624.
The extracellular domain of integrin αvβ3 contains a receptor for thyroid hormone and hormone analogs. The integrin is amply expressed by tumor cells and dividing blood vessel cells. The proangiogenic properties of thyroid hormone and the capacity of the hormone to promote cancer cell proliferation are functions regulated nongenomically by the hormone receptor on αvβ3. An L-thyroxine (T4) analog, tetraiodothyroacetic acid (tetrac), blocks binding of T4 and 3,5,3′-triiodo-L-thyronine (T3) by αvβ3 and inhibits angiogenic activity of thyroid hormone. Covalently bound to a 200 nm nanoparticle that limits its activity to the cell exterior, tetrac reformulated as Nanotetrac has additional effects mediated by αvβ3 beyond the inhibition of binding of T4 and T3 to the integrin. These actions of Nanotetrac include disruption of transcription of cell survival pathway genes, promotion of apoptosis by multiple mechanisms, and interruption of repair of double-strand deoxyribonucleic acid breaks caused by irradiation of cells. Among the genes whose expression is suppressed by Nanotetrac are EGFR, VEGFA, multiple cyclins, catenins, and multiple cytokines. Nanotetrac has been effective as a chemotherapeutic agent in preclinical studies of human cancer xenografts. The low concentrations of αvβ3 on the surface of quiescent nonmalignant cells have minimized toxicity of the agent in animal studies.
PMCID: PMC4172128  PMID: 25258542
integrin; thyroid hormone; thyroxine; antiangiogenesis; proapoptosis
5.  Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects 
Journal of clinical pharmacology  2007;47(12):1508-1520.
The present investigation determined the molecular structure and the pharmacokinetic and pharmacodynamic profiles of oral unfractionated heparin containing oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino]caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of the orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, 3-way crossover, randomized, open-label study. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The pharmacodynamics of heparin were obtained from analysis of plasma anti–factor Xa, anti–factor IIa, activated partial thromboplastin time, and total tissue factor pathway inhibitor data. The molecular weight properties and the disaccharide composition of orally administered unfractionated heparin/SNAC and parenterally administered unfractionated heparin are identical and consistent with the starting pharmaceutical standard heparin. Furthermore, the anti–factor Xa/anti–factor IIa ratio achieved is of approximately 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes.
PMCID: PMC4135515  PMID: 18048572
Oral heparin; anticoagulants; pharmacokinetics; pharmacodynamics; solid dosage form; heparin composition
6.  Ionic Liquid-Derived Blood-Compatible Composite Membranes for Kidney Dialysis 
A novel heparin- and cellulose-based biocomposite is fabricated by exploiting the enhanced dissolution of polysaccharides in room temperature ionic liquids (RTILs). This represents the first reported example of using a new class of solvents, RTILs, to fabricate blood-compatible biomaterials. Using this approach, it is possible to fabricate the biomaterials in any form, such as films or membranes, fibers (nanometer- or micron-sized), spheres (nanometer- or micron-sized), or any shape using templates. In this work, we have evaluated a membrane film of this composite. Surface morphological studies on this biocomposite film showed the uniformly distributed presence of heparin throughout the cellulose matrix. Activated partial thromboplastin time and thromboelastography demonstrate that this composite is superior to other existing heparinized biomaterials in preventing clot formation in human blood plasma and in human whole blood. Membranes made of these composites allow the passage of urea while retaining albumin, representing a promising blood-compatible biomaterial for renal dialysis, with a possibility of eliminating the systemic administration of heparin to the patients undergoing renal dialysis.
PMCID: PMC4129660  PMID: 16637031
biomaterials; heparin; renal dialysis; ionic liquids; cellulose
8.  Blood Compatible Carbon Nanotubes – Nano-based Neoproteoglycans 
Although nanotechnology has provided a rich variety of nanomaterials (1–100 nm) for in vivo medical applications, the blood compatibility of all these nanobiomaterials is still largely unexamined. Here, we report the preparation of blood-compatible carbon nanotubes (CNTs) that potentially represent the building blocks for nanodevices having in vivo applications. Activated partial thromboplastin time (APTT) and thromboelastography (TEG) studies prove that heparinization can significantly enhance the blood compatibility of nanomaterials.
PMCID: PMC4114241  PMID: 16584210
9.  Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standar d low-molecular-weight heparin, enoxaparin 
Thrombosis and haemostasis  2006;96(6):816-821.
Low-molecular-weight heparins (LMWH) exhibit potent anti-coagulant efficacy via their plasmatic effects on thrombin and factor Xa.These agents are also effective in releasing endothelial tissue factor pathway inhibitor (TFPI), the natural inhibitor of tissue factor, and exhibit significant anti-metastatic effects in experimental animal models. However, the potential for bleeding complications has slowed down the more widespread adoption of LMWH therapy in cancer patients. In this study, the effect of a non-anticoagulant form of LMWH (NA-LMWH) on experimental lung metastasis and tumor cell-induced platelet aggregation in vivo was compared to the LMWH enoxaparin. Using the B16 melanoma mouse model of metastasis, subcutaneous (s.c.) injection of NA-LMWH or enoxaparin (10 mg/kg), three hours before intravenous (i.v.) injection of metastatic melanoma cells, followed by daily doses for 14 days, reduced lung tumor formation by 70% (P<0.001). l.v. injection of tumor cells resulted in a significant (50–62%, P<0.01) fall in platelet counts. Pre-injection (i.v.) of enoxaparin completely abolished the tumor cell-induced thrombocytopenia, whereas NA-LMWH had no effect. Four hours after a single s.c. dose, enoxaparin but not NA-LMWH prolonged the clotting time three-fold and delayed the time to clot initiation more than 10-fold as measured by a Sonoclot analyzer and by thromboelastography, respectively. Enoxaparin but not NA-LMWH demonstrated a significant anti-coagulant effect in mice. Both NA-LMWH and enoxaparin caused similar TFPI release from endothelial cells in vitro. These data provide evidence to support the potential of NA-LMWH as an anti-metastatic agent without any significant impact on coagulation.
PMCID: PMC4114246  PMID: 17139378
Heparin; low-molecular-weight heparin; metastasis; anticoagulant
10.  Effects of Low-Dose Aspirin and Fish Oil on Platelet Function and NF-kappaB in Adults with Diabetes Mellitus 
Many diabetics are insensitive to aspirin’s platelet anti-aggregation effects. The possible modulating effects of coadministration of aspirin and fish oil in subjects with diabetes are poorly characterized.
Participants and Methods
Thirty adults with type 2 diabetes mellitus were treated with aspirin 81 mg/d for 7 days, then with fish oil 4g/day for 28 days, then the combination of fish oil and aspirin for another 7 days.
Aspirin alone and in combination with fish oil reduced platelet aggregation in most participants. Five of 7 participants classified as aspirin insensitive 1 week after daily aspirin ingestion were sensitive after the combination. Although some platelet aggregation measures correlated positively after aspirin and fish oil ingestion alone and (in combination) in all individuals, correlation was only observed in those who were aspirin insensitive after ingestion of the combination.
Co-adminstration of aspirin and fish oil may reduce platelet aggregation more than aspirin alone in adults with diabetes mellitus.
PMCID: PMC3683095  PMID: 23664596
Omega-3 fatty acids; eicosapentaenoic acid; docosahexaenoic acid; aspirin; acetylsalicylic acid; platelet function; NF-kappaB; nuclear factor kappa-light-chain-enhancer of activated B cells
11.  Cancer Cell Gene Expression Modulated from Plasma Membrane Integrin αvβ3 by Thyroid Hormone and Nanoparticulate Tetrac 
Integrin αvβ3 is generously expressed by cancer cells and rapidly dividing endothelial cells. The principal ligands of the integrin are extracellular matrix proteins, but we have described a cell surface small molecule receptor on αvβ3 that specifically binds thyroid hormone and thyroid hormone analogs. From this receptor, thyroid hormone (l-thyroxine, T4; 3,5,3′-triiodo-l-thyronine, T3) and tetraiodothyroacetic acid (tetrac) regulate expression of specific genes by a mechanism that is initiated non-genomically. At the integrin, T4 and T3 at physiological concentrations are pro-angiogenic by multiple mechanisms that include gene expression, and T4 supports tumor cell proliferation. Tetrac blocks the transcriptional activities directed by T4 and T3 at αvβ3, but, independently of T4 and T3, tetrac modulates transcription of cancer cell genes that are important to cell survival pathways, control of the cell cycle, angiogenesis, apoptosis, cell export of chemotherapeutic agents, and repair of double-strand DNA breaks. We have covalently bound tetrac to a 200 nm biodegradable nanoparticle that prohibits cell entry of tetrac and limits its action to the hormone receptor on the extracellular domain of plasma membrane αvβ3. This reformulation has greater potency than unmodified tetrac at the integrin and affects a broader range of cancer-relevant genes. In addition to these actions on intra-cellular kinase-mediated regulation of gene expression, hormone analogs at αvβ3 have additional effects on intra-cellular protein-trafficking (cytosol compartment to nucleus), nucleoprotein phosphorylation, and generation of nuclear coactivator complexes that are relevant to traditional genomic actions of T3. Thus, previously unrecognized cell surface-initiated actions of thyroid hormone and tetrac formulations at αvβ3 offer opportunities to regulate angiogenesis and multiple aspects of cancer cell behavior.
PMCID: PMC4290672  PMID: 25628605
integrin; thyroid hormone; tetraiodothyroacetic acid; nanoparticle; gene transcription
12.  The combination of EPA+DHA and low-dose aspirin ingestion reduces platelet function acutely whereas each alone may not in healthy humans 
Aspirin’s effectiveness in reducing cardiovascular disease events is inadequate in some individuals, a phenomenon termed aspirin “resistance”. The hypothesis that combining low dose aspirin with eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) reduces platelet function in the acute setting has not been investigated.
Patients and methods
We conducted a clinical trial of EPA+DHA and aspirin ingestion in healthy adults. Fasting blood samples were drawn at baseline and 4 h after supplementation with EPA/DHA (3.4 g/d), aspirin (81 mg), and both. Platelet function was measured using the Platelet Function Analyzer-100 (PFA-100). Plasma lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), autotaxin, angiogenesis activators, and cytokines were measured.
Platelet function decreased with the combination of aspirin+EPA/DHA (p=0.03) but not with either alone (p>0.05). EPA-LPC increased (p=0.002).
Discussion and conclusions
Our results demonstrate that a potentially beneficial effect on platelet function occurred within 4 h after ingestion of low-dose aspirin and EPA+DHA in healthy adults.
PMCID: PMC3589139  PMID: 23017325
Omega-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Aspirin; Acetylsalicylic acid; Platelet function; Platelet function analyzer-100
13.  Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area 
Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.
PMCID: PMC3848639  PMID: 24044606
Anemia; Chelation; Arabian Gulf; Iron chelation therapy; Iron overload; Thalassemia management; Transfusion
14.  Effects of Obesity and Sex on Antimicrobial Pharmacokinetics and Acute Kidney Injury: Validation of a Preclinical Model 
Obese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n = 40) and obesity-resistant (n = 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC0–24) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.
PMCID: PMC3553709  PMID: 23147732
15.  Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix 
Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors.
PMCID: PMC3657431  PMID: 23737792
16.  Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration 
Wet age-related macular degeneration (AMD) is the most common reason for vision loss in the United States. Many treatments, such as laser therapy and photodynamic therapies, have been used but their efficacy is limited. Emerging anti-vascular endothelial growth factor (VEGF) therapies are now considered the standard of care. Anti-VEGF agents inhibit angiogenesis in the eye by suppressing abnormal blood vessel growth, leading to vision improvement. Ranibizumab and bevacizumab are two examples of anti-VEGF drugs that have been approved; both showed promise based on the visual acuity scale. Aflibercept, another new therapy known to trap VEGF and inhibit multiple growth factors, is promising not only because it can be taken bimonthly based on year 1 of the VIEW trials, but it can also be extended, as demonstrated in year 2 of the VIEW trials. Based on a cost–effect analysis, aflibercept is comparable to other leading therapies. This is a review of relevant clinical trials that have proven the non-inferiority and safety of aflibercept compared to the standard of care and its unique role in the current management of wet AMD.
PMCID: PMC3595183  PMID: 23503202
aflibercept; VEGF; anti-VEGF; pegatanib; bevacizumab; ranibizumab; VIEW trials
17.  Adsorption of doxorubicin on poly (methyl methacrylate) -chitosan-heparin coated activated carbon beads 
Langmuir  2012;28(9):4396-4403.
Extracorporeal filter cartridges, filled with activated carbon bead (ACB) adsorbent, have been used for removal of overdosed cancer drugs from the blood. Coatings on adsorbent matrices, poly (methyl methacrylate) (PMMA)/activated carbon bead and PMMA/chitosan/heparin/ACB composites, were tested to improve their biocompatibility and blood compatibility. PMMA coating on ACBs was accomplished in a straightforward manner using a PMMA solution in ethyl acetate. One-step hybrid coating of ACBs with PMMA-anticoagulant heparin required the use of acetone and water co-solvents. Multi-layer coatings with three components, PMMA, chitosan, and heparin involved three steps: PMMA was first coated on ACBs; chitosan was then coated on the PMMA coated surface; and finally heparin was covalently attached to the chitosan coating. Surface morphologies were studied by scanning electron microscopy. X-ray photoelectron spectroscopy confirmed −SO3− group. Adsorption, of a chemotherapy drug (doxorubicin) from both water and PBS, by the coated ACBs was examined. The adsorption isotherm curves were fitted using the Freundlich model. The current adsorption system might find potential applications in the removal of high dose regional chemotherapy drugs while maintaining high efficiency, biocompatibility, and blood compatibility.
PMCID: PMC3309418  PMID: 22313019
doxorubicin; drug removal; carbon beads; adsorption; heparin coating; blood compatibility
18.  The Effects of EPA+DHA and Aspirin on Inflammatory Cytokines and Angiogenesis Factors 
In a recent study, we showed that the combination of aspirin plus the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) synergistically inhibited platelet function. As aspirin, EPA, and DHA have demonstrated anti-inflammatory properties, we hypothesized that the ingestion of EPA and DHA, with and without aspirin, would reduce plasma levels of inflammatory cytokines and angiogenesis factors more than aspirin alone and before aspirin was ingested.
Using multiplex technology, we investigated the effects of aspirin (single-dose 650 mg on day 1), EPA+DHA (3.4 g/d for days 2-29), and aspirin with EPA+DHA (day 30) on plasma levels of inflammatory cytokines and angiogenesis factors in healthy adults.
Aspirin alone had no effect on any factor versus baseline, but EPA+DHA, with and without aspirin, significantly reduced concentrations of 8 of 9 factors. Although EPA+DHA plus aspirin reduced concentrations of a subset of the factors compared to baseline, neither aspirin alone nor the combination significantly reduced the level of any analyte more robustly than EPA+DHA alone.
These data suggest that EPA+DHA has more pronounced down-regulatory effects on inflammation and angiogenesis than aspirin. The implications of these findings for the use of combined therapy for cardiovascular disease remain to be clarified.
PMCID: PMC3331709  PMID: 22530200
eicosapentaenoic acid; docosahexaenoic acid; lipid mediators; fatty acids; angiogenesis; hemostasis; platelet function; cytokines; aspirin
19.  Current primary open-angle glaucoma treatments and future directions 
Primary open-angle glaucoma (POAG) is a leading cause of blindness with no known cure. Management of the disease focuses on lowering intraocular pressure (IOP) with current classes of drugs like prostaglandin analogs, beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors. These treatments have not helped all patients. Some patients continue to experience deterioration in the optic nerve even though their IOPs are within the normal range. New views have surfaced about other pathophysiological processes (such as oxidative stress, vascular dysfunction, and retinal cell apoptosis) being involved in POAG progression, and adjunctive treatments with drugs like memantine, bis(7)-tacrine, nimodipine, and mirtogenol are advocated. This review examines the current and proposed treatments for POAG. Some of the proposed drugs (bis(7)-tacrine, nimodipine, vitamin E, and others) have shown good promise, mostly as monotherapy in various clinical trials. It is recommended that both the current and proposed drugs be put through further robust trials in concurrent administration and evaluated.
PMCID: PMC3484725  PMID: 23118520
bis(7)-tacrine; betaxolol; memantine; mirtogenol; POAG; timolol; travoprost
20.  Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins 
Science (New York, N.Y.)  2011;334(6055):498-501.
Ultralow molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.
PMCID: PMC3425363  PMID: 22034431
21.  Ultraperformance ion-pairing liquid chromatography with on-line electrospray ion trap mass spectrometry for heparin disaccharide analysis 
Analytical biochemistry  2011;415(1):59-66.
A high resolution method for the separation and analysis of disaccharides prepared from heparin and heparan sulfate (HS) using heparin lyases is described. Ultraperformance liquid chromatography in a reverse-phase, ion-pairing mode efficiently separates eight heparin/HS disaccharides. The disaccharides can then be detected and quantified using electrospray ionization mass spectrometry. This method is particularly useful in the analysis of small amounts of biological samples, including cells, tissues and biological fluids, as it provides high sensitivity without being subject to interference from proteins, peptides and other sample impurities.
PMCID: PMC3108029  PMID: 21530482
heparin; heparan sulfate; heparin lyase; disaccharide analysis; biological samples; ultraperformance liquid chromatography; mass spectrometry
22.  Control of the heparosan N-deacetylation leads to an improved bioengineered heparin 
The production of the anticoagulant drug heparin from non-animal sources has a number of advantages over the current commercial production of heparin. These advantages include better source material availability, improved quality control, and reduced concerns about animal virus or prion impurities. A bioengineered heparin would have to be chemically and biologically equivalent to be substituted for animal-sourced heparin as a pharmaceutical. In an effort to produce bioengineered heparin that more closely resembles pharmaceutical heparin, we have investigated a key step in the process involving the N-deacetylation of heparosan. The extent of N-deacetylation directly affects the N-acetyl/N-sulfo ratio in bioengineered heparin and also impacts its molecular weight. Previous studies have demonstrated that the presence and quantity of N-acetylglucosamine in the nascent glycosaminoglycan chain, serving as the substrate for the subsequent enzymatic modifications (C5 epimerization and O-sulfonation), can impact the action of these enzymes and, thus, the content and distribution of iduronic acid and O-sulfo groups. In this study, we control the N-deacetylation of heparosan to produce a bioengineered heparin with an N-acetyl/N-sulfo ratio and molecular weight that is similar to animal-sourced pharmaceutical heparin. The structural composition and anticoagulant activity of the resultant bioengineered heparin was extensively characterized and compared to pharmaceutical heparin obtained from porcine intestinal mucosa.
PMCID: PMC3124281  PMID: 21484210
Heparin; Heparosan; Porcine intestine; Deacetylation
23.  High Density Lipoprotein (HDL) Modulation Targets 
Drugs of the future  2010;35(1):33-39.
Given the strong genetic determinants of favorable HDL-C levels, the ability to procure the cardiovascular disease and longevity benefits associated with this mediator of the reverse cholesterol transport pathway through pharmaceutical intervention is challenging. Niacin is still the most robust HDL-C raising pharmaceutical agent on the market at its use leads to elevations up to 35%. Cholesteryl ester transfer protein (CETP) and endothelial lipase (EL) are two targets involved in the reverse cholesterol transport pathway that have become therapeutic targets of various investigations for raising HDL. However, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was stopped in December 2006 due to excess mortality in the group of patients treated with torcetrapib, a CETP inhibitor. Other CETP inhibitors being studied include anacetrapib and JTT-705. Other CEPT inhibitors including TA-8995, DRL-17822, JTT-302, and others are under investigation. Additionally a biologic target CETi-1, an investigational vaccine in phase II development designed to elicit antibodies that bind and inhibit the activity of CETP leading to blocking the ability of the protein to transfer cholesterol from HDL to LDL and thus causing HDL cholesterol levels to rise is under clinical investigation for sometime.
PMCID: PMC3381456  PMID: 22740724
High Density lipoprotein (HDL); Low Density lipoprotein (LDL); atherosclerosis; coronary heart disease (CHD); Cholesteryl ester transfer protein (CETP); Endothelial Lipase; Longevity; Stroke; Coronary artery Diseases (CAD); cardiovascular diseases (CVD); Inflammation; genetics; niacin; statins; fibrates
24.  Novel Therapeutic Targets for Preserving a Healthy Endothelium: Strategies for Reducing the Risk of Vascular and Cardiovascular Disease 
Cardiology Journal  2011;18(4):352-363.
The endothelium lies in a strategic anatomical position between the circulating blood and vascular smooth-muscle cells as a source of vasodilators such as nitric oxide, prostacyclin, and hyperpolarizing factor as well as heparin-like substances as well as other molecules with anti-proliferative properties. These effects of endothelial cells may explain why platelets and monocytes usually do not adhere at the blood vessel wall. However, under pathological conditions, endothelial dysfunction occurs and significantly contributes to the increase of platelet-vessel wall interaction, vasoconstriction, pro-inflammation, and proliferation. Under these conditions, endothelium-dependent vasodilation is reduced and endothelium-dependent constrictor responses are augmented. Upon vessel wall injury platelets rapidly adhere to the exposed sub-endothelial matrix which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates forming a stable platelet plug. Therapeutic strategies aimed at improving or preserving endothelial function therefore may be promising in the prevention and treatment of coronary artery disease. Diagnostic modalities for assessment of endothelial function should allow for the early detection of vascular endothelial dysfunction before the manifestation of serious adverse vascular disorders.
PMCID: PMC3342824  PMID: 21769815
vascular; endothelial cell; cardiovascular disorders; coronary syndrome; vasoconstriction; vasodilation; inflammation; anti-inflammation; anti-platelet; pro-platelet; anticoagulant; pro-coagulant; Diagnosis of endothelial function
25.  Current status and future directions in the management of chronic hepatitis C 
Virology Journal  2012;9:57.
Hepatitis C virus (HCV) is endemic worldwide, and it causes cirrhosis and other complications that often lead to death; nevertheless, our knowledge of the disease and its mechanisms is limited. HCV is most common in underdeveloped nations, including many in Africa and Asia. The virus is usually transmitted by parenteral routes, but sexual, perinatal, and other types of transfer have been known to occur. Approximately 80% of individuals who contract hepatitis C develop a chronic infection, and very few are able to spontaneously clear the virus. Because hepatitis C is asymptomatic in the majority of patients, the presence of HCV RNA in the serum is the best diagnostic tool. Although serious complications from hepatitis C may not occur for 20 years, 1/5 of chronic patients eventually develop life - threatening cirrhosis. More research is needed on the different therapy options for the disease, and many factors, most importantly the genotype of the virus, must be taken into account before beginning any treatment. As there is no vaccine against HCV at present, the most effective and recommended therapy is pegylated-interferon-α-2a plus ribavirin. While interferon is marginally effective as a monotherapy, both adding the moiety and combining it with ribavirin have been shown to dramatically increase its potency. While there are numerous alternative and complementary medicines available for patients with hepatitis C, their efficacy is questionable. Currently, research is being done to investigate other possible treatments for hepatitis C, and progress is being made to develop a vaccine against HCV, despite the many challenges the virus presents. Until such a vaccination is available, prevention and control methods are important in containing and impeding the spread of the virus and mitigating its deleterious effects on the health of people and communities worldwide.
PMCID: PMC3325870  PMID: 22385500
Hepatitis C; Fibrosis; Cirrhosis; Hepatic carcinoma; Prevention; Treatment; Antiviral

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