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.
aflibercept; VEGF; anti-VEGF; pegatanib; bevacizumab; ranibizumab; VIEW trials
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.
doxorubicin; drug removal; carbon beads; adsorption; heparin coating; blood compatibility
Omega-3 [(n-3)] fatty acids have been linked to healthy aging throughout life. Recently, fish-derived omega-3 fatty acids EPA and DHA have been associated with fetal development, cardiovascular function, and Alzheimer’s disease. However, because our bodies do not efficiently produce some omega-3 fatty acids from marine sources, it is necessary to obtain adequate amounts through fish and fish-oil products. Studies have shown that EPA and DHA are important for proper fetal development, including neuronal, retinal, and immune function. EPA and DHA may affect many aspects of cardiovascular function including inflammation, peripheral artery disease, major coronary events, and anticoagulation. EPA and DHA have been linked to promising results in prevention, weight management, and cognitive function in those with very mild Alzheimer’s disease.
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.
eicosapentaenoic acid; docosahexaenoic acid; lipid mediators; fatty acids; angiogenesis; hemostasis; platelet function; cytokines; aspirin
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.
bis(7)-tacrine; betaxolol; memantine; mirtogenol; POAG; timolol; travoprost
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.
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.
heparin; heparan sulfate; heparin lyase; disaccharide analysis; biological samples; ultraperformance liquid chromatography; mass spectrometry
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.
Heparin; Heparosan; Porcine intestine; Deacetylation
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.
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
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.
vascular; endothelial cell; cardiovascular disorders; coronary syndrome; vasoconstriction; vasodilation; inflammation; anti-inflammation; anti-platelet; pro-platelet; anticoagulant; pro-coagulant; Diagnosis of endothelial function
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.
Hepatitis C; Fibrosis; Cirrhosis; Hepatic carcinoma; Prevention; Treatment; Antiviral
The stability of a formulated heparin was examined during its sterilization by autoclaving. A new method to follow loss in heparin binding to the serine protease inhibitor, antithrombin III, and the serine protease, thrombin, and was developed using a surface plasmon resonance (SPR) competitive binding assay. This loss in binding affinity correlated well with loss in anti-factor IIa (thrombin) activity as well as anti-factor Xa activity as measured using conventional amidolytic assays. Autoclaving also resulted in a modest breakdown of the heparin backbone as confirmed by a slight reduction in number averaged and weight averaged molecular weight and an increase in polydispersity. While no clear changes were observed by nuclear magnetic resonance spectroscopy, disaccharide composition analysis using high-performance liquid chromatography-electrospray ionization mass spectrometry suggested loss of selected sulfo groups had taken place. It is this sufo group loss that probably accounts for a decrease in the binding of autoclaved heparin to antithrombin III and thrombin as well as the observed decrease in its amidolytic activity.
heparin; surface plasmon resonance; antithrombin III; thrombin; interaction; stability; autoclaving
A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10−7 M), T4 significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T4 and T3 to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T4>T3) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T4-induced, but not T3-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.
With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.
The hypothesis that cancers arise from a small population of cells, called cancer stem cells (CSCs), is gaining more popularity amongst researchers. There are, however, still many skeptics who bring into question the validity of this theory. Many skeptics believe that there is not a specific subset of cells that originate with these characteristics, but that they develop certain features over time making them more resistant to conventional therapy. It is theorized that many of the relapses occurring after remission are due to our inability to destroy the self-renewing CSCs. This central idea, that CSCs are biologically different from all other cancer cells, has directed research towards the development of therapy to target CSCs directly. The major dilemma in targeting therapy in myeloproliferative disorders, malignancies of the central nervous system or malignancies in general, is the inability to target CSCs as opposed to normal stem cells. However, with the recent advances in the identifications of unique molecular signatures for CSCs along with ongoing clinical trials targeting CSCs, it is possible to use targeted nanotechnology-based strategies in the management of different types of cancers.
Cancer Stem Cell; Cancer Stem Cell Like; Molecular Signature; Cell Surface Markers; Microenvironment; Targeted Therapy; Chemoresistance; Cancer Recurrence; Signaling Pathways
Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.
Clinical treatment protocols for specific solid cancers have favorable response rates of 20%–25%. Cancer cells frequently become resistant to treatment. Therefore, novel anti-cancer drugs and combination regimens need to be developed. Conducting enough clinical trials to evaluate combinations of anti-cancer agents in several regimens to optimize treatment is not feasible. We showed that tetrac inhibits the growth of various cancer cell lines. Our newly developed in vitro system allowed studying the effects of tetrac over time in various human cancer cell lines. Our mathematical model could distinguish two effects of tetrac and may be used to predict effects of other than the studied dosage regimens. Human breast cancer cells were more sensitive to the effect on success of replication than the effect on growth rate, whereas the maximum possible effect was larger for the latter effect. Nanoparticulate tetrac, which does not enter into cells, had a larger effect than unmodified tetrac. The combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab showed approximately additive effects. Our in vitro perfusion system together with mathematical modeling may be useful for dose-finding, translation from in vitro to animal and human studies, and studying effects of other chemotherapeutic agents or their combinations.
The pathophysiology of brain damage that is common to ischemia–reperfusion injury and brain trauma include disodered neuronal and glial cell energetics, intracellular acidosis, calcium toxicity, extracellular excitotoxic glutamate accumulation, and dysfunction of the cytoskeleton and endoplasmic reticulum. The principal thyroid hormones, 3,5,3′-triiodo-l-thyronine (T3) and l-thyroxine (T4), have non-genomic and genomic actions that are relevant to repair of certain features of the pathophysiology of brain damage. The hormone can non-genomically repair intracellular H+ accumulation by stimulation of the Na+/H+ exchanger and can support desirably low [Ca2+]i.c. by activation of plasma membrane Ca2+–ATPase. Thyroid hormone non-genomically stimulates astrocyte glutamate uptake, an action that protects both glial cells and neurons. The hormone supports the integrity of the microfilament cytoskeleton by its effect on actin. Several proteins linked to thyroid hormone action are also neuroprotective. For example, the hormone stimulates expression of the seladin-1 gene whose gene product is anti-apoptotic and is potentially protective in the setting of neurodegeneration. Transthyretin (TTR) is a serum transport protein for T4 that is important to blood–brain barrier transfer of the hormone and TTR also has been found to be neuroprotective in the setting of ischemia. Finally, the interesting thyronamine derivatives of T4 have been shown to protect against ischemic brain damage through their ability to induce hypothermia in the intact organism. Thus, thyroid hormone or hormone derivatives have experimental promise as neuroprotective agents.
thyroid hormone; thyronamines; sodium-proton exchanger; calcium ATPase; seladin-1; transthyretin; ischemia–reperfusion injury
Chemoprevention, especially through the use of naturally occurring phytochemicals capable of impeding the process of one or more steps of carcinogenesis process, is a promising approach for cancer management. Despite promising results in preclinical settings, its applicability to humans has met with limited success largely due to inefficient systemic delivery and bioavailability of promising chemopreventive agents. Here, we introduce the concept of nanochemoprevention, which uses nanotechnology for enhancing the outcome of chemoprevention. We encapsulated green tea polyphenol epigallocatechin-3-gallate (EGCG) in polylactic acid–polyethylene glycol nanoparticles and observed that encapsulated EGCG retains its biological effectiveness with over 10-fold dose advantage for exerting its proapoptotic and angiogenesis inhibitory effects, critically important determinants of chemopreventive effects of EGCG in both in vitro and in vivo systems. Thus, this study could serve as a basis for the use of nanoparticle-mediated delivery to enhance bioavailability and limit any unwanted toxicity of chemopreventive agents, such as EGCG.
There is wide individual variability in the pharmacokinetics, pharmacodynamics, and tolerance to anticancer drugs within the same ethnic group and even greater variability among different ethnicities. Pharmacogenomics (PG) has the potential to provide personalized therapy based on individual genetic variability in an effort to maximize efficacy and reduce adverse effects. The benefits of PG include improved therapeutic index, improved dose regimen, and selection of optimal types of drug for an individual or set of individuals. Advanced or metastatic breast cancer is typically treated with single or multiple combinations of chemotherapy regimens including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs, vinca alkaloids, and others. In this review, the PG of breast cancer therapeutics, including tamoxifen, which is the most widely used therapeutic for the treatment of hormone-dependent breast cancer, is reviewed. The pharmacological activity of tamoxifen depends on its conversion by cytochrome P450 2D6 (CYP2D6) to its abundant active metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the coadministration of other drugs that inhibit CYP2D6 function, produce little endoxifen and hence derive limited therapeutic benefit from tamoxifen; the same can be said about the different classes of therapeutics in breast cancer. PG studies of breast cancer therapeutics should provide patients with breast cancer with optimal and personalized therapy.
pharmacogenomics; genetic; pharmacokinetic; pharmacodynamic; personalized medicine; pharmacotherapy; anticancer drugs; efficacy; safety
The novel low molecular weight chitosan polysulfate (MW 5,120–26,200 Da) was prepared using the depolymerization of chitosan with papain (EC. 18.104.22.168). The sulfonation of depolymerized products was performed using chlorosulfonic acid in N, N-dimethylformamide under semi-heterogeneous conditions. The structures of the products were characterized by FTIR, 13C NMR, and 1H NMR (1D, 2D NMR) spectroscopy. The present study sheds light on the mechanism of anticoagulant activity of chitosan polysulfate. Anticoagulant activity was investigated by an activated partial thromboplastin assay, a thrombin time assay, a prothrombin time assay and thrombelastography. Surface plasmon resonance also provided valuable data for understanding the relationship between the molecular binding of sulfated chitosan to two important blood clotting regulators, antithrombin III and heparin cofactor II. These results show that the principal mechanism by which this chitosan polysulfate exhibits anticoagulant activity is mediated through heparin cofactor II and is dependent on polysaccharide molecular weight.
Antibiotics offer great benefits by reducing the duration and severity of illnesses and aiding in infection transmission control. With this being said, the inexorable process of antimicrobial drug resistance is to some degree unavoidable. Although drug resistance will likely persist and is to be expected, the overall level can be dramatically decreased with increased attention to antibiotic overuse and the pharmacokinetic and pharmacodynamic properties of different drug formulations, and the use of proper hygiene and protective barriers. Implementation of such practices as microbial surveillance and prophylaxis has been shown to result in decreased hospital length of stay, health care costs and mortality due to drug-resistant infections. This review will summarize current progress in preventative techniques aimed at reducing the incidence of infection by antimicrobial-resistant bacteria and the emergence and spread of antimicrobial-resistant strains. By employing a variety of prevention strategies, including proper personal hygiene, prescreening for carrier status before hospital admission, disinfection of hospital rooms, and careful monitoring of antimicrobial prescribing, marked progress can be achieved in the control of drug-resistant pathogens, which can translate into more effective antimicrobial therapy.
infection prevention; antibiotic; personal hygiene; disinfection; microbial surveillance; drug-resistant pathogen
Silver nanoparticles exhibit unique antibacterial properties that make these ideal candidates for biological and medical applications. We utilized a clean method involving a single synthetic step to prepare silver nanoparticles that exhibit antimicrobial activity.
Materials & methods
These nanoparticles were prepared by reducing silver nitrate with diaminopyridinylated heparin (DAPHP) and hyaluronan (HA) polysaccharides and tested for their efficacy in inhibiting microbial growth.
Results & discussion
The resulting silver nanoparticles exhibit potent antimicrobial activity against Staphylococcus aureus and modest activity against Escherichia coli. Silver–HA showed greater antimicrobial activity than silver–DAPHP, while silver–glucose nanoparticles exhibited very weak antimicrobial activity. Neither HA nor DAPHP showed activity against S. aureus or E. coli.
These results suggest that DAPHP and HA silver nanoparticles have potential in antimicrobial therapeutic applications.
antimicrobial; Escherichia coli; silver heparin nanoparticles; silver hyaluronan nanoparticles; silver nanoparticles; Staphylococcus aureus
Metal nanoparticles have been studied for their anticoagulant and anti-inflammatory efficacy in various models. Specifically, gold and silver nanoparticles exhibit properties that make these ideal candidates for biological applications. The typical synthesis of gold and silver nanoparticles incorporates contaminants that could pose further problems. Here we demonstrate a clean method of synthesizing gold and silver nanoparticles that exhibit biological functions. These nanoparticles were prepared by reducing AuCl4 and AgNO3 using heparin and hyaluronan, as both reducing and stabilizing agents. The particles show stability under physiological conditions, and narrow size distributions for heparin particles and wider distribution for hyaluronan particles. Studies show that the heparin nanoparticles exhibit anticoagulant properties. Additionally, either gold- or silver- heparin nanoparticles exhibit local anti-inflammatory properties without any significant effect on systemic hemostasis upon administration in carrageenan-induced paw edema models. In conclusion, gold and silver nanoparticles complexed with heparin demonstrated effective anticoagulant and anti-inflammatory efficacy, having potential in various local applications.
Current lipid management guidelines are focused on decreasing low-density lipoprotein (LDL-C) levels as the primary target for reducing coronary heart disease (CHD) risk. Yet, many recent studies suggest that low levels of high-density lipoprotein (HDL-C) are a major independent risk factor for cardiovascular diseases. According to several clinical trials, a 1% increase in HDL-C is associated with a 0.7%–3% decrease in CHD events. The direct link between high levels of triglycerides (TG) and CHD, on the other hand, is less well defined. A large reduction in TG is needed to show a difference in CHD events, especially in men. Evidence for a shift in lipid management toward targeting both LDL-C and HDL-C as primary targets for therapy is presented. Currently, the 3-hydroxy-3-methylgutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors) have proven to significantly decrease LDL-C levels, reduce CHD morbidity/mortality and improve overall survival. However, improvement of survival with statins may be due to other pleiotropic effects beyond LDL-C lowering. Fibric acid derivatives and niacin are primarily used to increase HDL-C levels, although with side effects. Future therapies targeting HDL-C may have profound results on reducing CHD morbidity and mortality. This article highlights existing and future targets in lipid management and is based on available clinical data. There is an urgent need for new treatments using a combination of drugs targeting both LDL-C and HDL-C. Such treatments are expected to have a superior outcome for dyslipidemia therapy, along with TG management.
cholesterol; lipid; LDL-C; HDL-C; triglycerides; statin; nicotinic acid; fibric acid; atherosclerosis; coronary heart diseases
A series of reports in the past decade have ascribed pro-angiogenic activity to several thyroid hormone analogues, including L-thyroxine (T4), 3,5,3-triiodo-L-thyronine (T3) and diiodothyropropionic acid (DITPA). Model systems of angiogenesis have demonstrated that thyroid hormone-induced neovascularization is initiated at a cell surface receptor for the hormone on an integrin. The hormone signal is transduced within the cell by extracellular regulated kinase 1/2 (ERK1/2) into secretion of basic fibroblast growth factor (bFGF) and other vascular growth factors and consequent angiogenesis. Intact animal studies have shown that endogenous thyroid hormone supports blood vessel density in heart and brain and that thyroid hormone administration can induce angiogenesis in ischemic limbs.
Overactive bladder syndrome (OAB) refers to individuals with the following symptoms: urinary urgency, increased urinary frequency, and urge incontinence. These symptoms are not life threatening but can cause embarrassment and significantly impact quality of life. There are numerous treatment options for OAB, including behavioral therapy, traditional pharmacological therapy or a combination of the two. These options are considered the mainstay of treatment for OAB. We carried out a comprehensive systematic review of the available literature on the effectiveness of behavioral intervention, anticholinergic drugs, and their combination in the management of adults with overactive bladder, with emphasis on results from clinical trials and primary literature. Each treatment intervention is efficacious, and the choice should be based on the patient's severity of symptoms, tolerability, compliance and satisfaction with the treatment. Based on available literature, management of OAB using a combination of behavioral therapy and drug intervention is the most efficacious in terms of patient satisfaction, perceived improvement, and reduction of bladder symptoms. It is also the most practical and cost effective for optimal management of patients with OAB. Pharmacological treatment, in addition to behavioral therapy, remains important in the management of adults with OAB syndrome.