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Biomedical subjects

Israel Rubinstein

Publications and source records attributed to Israel Rubinstein.

At least 37 records · Page 2Linked to original sources
PubMed2005

Human VIP-alpha: an emerging biologic response modifier to treat primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a rare life-threatening disorder of unknown etiology manifested by chronic elevation of pulmonary arterial pressure. Given that pulmonary vasoconstriction, endothelial and vascular smooth muscle cell proliferation and in situ thrombosis contribute appreciably to the evolution of PPH, treatment with vasodilators, antiproliferative drugs and anticoagulants, alone or in combination, constitute the pharmacologic standard of care. To this end, long-term administration of oral calcium channel blockers, prostacyclin analogs by various routes and oral endothelin-1 receptor antagonists, alone or in combination, is efficacious in treating patients with PPH. Unfortunately, efficacy is hampered by poor stability, delivery and bioavailability, and by systemic toxicity. Hence, there is an ongoing need to develop and test new drugs to treat patients with PPH. To address this issue, a novel, targeted, long-acting, biocompatible and safe sterically stabilized liposomal and micellar formulation of human vasoactive intestinal peptide (VIP) was developed and tested for human use: the 28-amino acid pleiotropic biologic response modifier, human VIP-alpha. The long-lasting salutary effects of phospholipid-associated VIP on vasomotor tone and arterial pressure were expressed at low concentrations solely in diseased animals and were independent of its route of administration. Thus, the author proposes that human VIP-alpha could be developed as a safe long-acting drug to treat patients with PPH.

Humans↗
PubMed2004

Layer-by-layer assembly of ordinary and composite coordination multilayers.

Coordination self-assembly of bishydroxamate-based metal-organic multilayers on gold employing a layer-by-layer (LbL) approach was investigated. It is shown that the solution chemistry of the participating metal ion has a marked influence on the composition and properties of the multilayers. Use of Ce4+ and particularly zirconium(IV) acetylacetonate (Zr(acac)4) solutions in the ion-binding step of multilayer construction leads to multilayers with a near-stoichiometric metal ion-to-ligand ratio, suggesting a structure close to that predicted by a simple coordination self-assembly scheme. On the other hand use of a ZrCl4 solution as the source of metal ions in the multilayer construction leads to a multilayer with greater thickness and a large excess of Zr(IV), evenly distributed between the organic layers. In the latter case, a ratio of ca. 1:2 between the excess Zr and oxygen, as well as long-term Zr4+ binding experiments showing deposition of ZrO2, suggest the formation of a zirconia-type nanophase between the bishydroxamate organic repeat units during multilayer self-assembly. Hence, while the multilayer prepared using Zr(acac)4 solution appears to represent a "true" coordination-based structure, the one prepared using ZrCl4 is best described as a composite organic-ceramic multilayer. Composite multilayers prepared in this way display different properties from those of the stoichiometric ones, such as improved dielectric behavior and higher stiffness. Even greater mechanical stability is obtained with multilayers constructed using alternate binding of ZrCl4 and Ce4+. The concept of LbL formation of coordination-based composite organic-ceramic structures may be useful in obtaining nanometer-scale structures with tunable properties.

Cesium↗
PubMed2004

Biological sensing using transmission surface plasmon resonance spectroscopy.

Ultrathin gold island films evaporated on transparent substrates offer promising transducers for chemical and biological sensing in the transmission surface plasmon resonance (T-SPR) mode. In the present work, the applicability of T-SPR-based systems to biosensing is demonstrated, using a well-established biological model system. Au island films were evaporated on polystyrene slides and modified with a biotinylated monolayer via a multistep surface reaction, the latter assisted by the good adhesion of metal islands to polystyrene. The biotin-derivatized Au island film was then used as a biological recognition surface for selective sensing of avidin binding, distinguishing between specific and nonspecific binding to the substrate. Transduction of the binding event into an optical signal was achieved by T-SPR spectroscopy, using plasmon intensity measurements, rather than wavelength change, for maximal sensitivity and convenience. T-SPR spectroscopy of Au island films is shown to be an effective tool for monitoring the binding of biological molecules to receptor layers on the Au surface and a promising approach to label-free optical biosensing.

Biosensing Techniques↗
PubMed2004

Widely-applicable gold substrate for the study of ultrathin overlayers.

Ultrathin films on gold substrates have been the subject of enormous scientific and technological interest. Comprehensive study of such systems requires concomitant application of a variety of complementary characterization techniques. The reliability of the result is frequently hampered by the fact that different characterization methods impose different requirements on the Au substrate, resulting in the need to use different types of Au substrates for different measurements, possibly influencing the overlayer structure. This results in an average, rather than exact, structure determination. Here, we show that 15-nm-thick Au films evaporated at 0.5 A/sec on silanized glass and annealed are semi-transparent, electrically conducting, and morphologically well-defined, showing a smooth, [111] textured surface. Such Au films provide a high-quality, widely applicable and relatively inexpensive platform for ultrathin overlayers, enabling characterization by a wide spectrum of experimental methods, applied to the same substrate. The exceptional qualities and analytical capabilities of such substrates are demonstrated with several different systems: (i) Cu underpotential deposition (upd); (ii) alkanethiol self-assembly; (iii) formation of Au nanoparticle layers; (iv) binding of the chromophore protoporphyrin IX (PPIX) to a monolayer of 11-mercaptoundecanoic acid (MUA). In the latter case it is shown that the use of Cu(2+) ions for binding between the carboxylate groups of PPIX and MUA promotes better organization of the porphyrin layer.

Glass↗
PubMed2004

Low-dose, long-term macrolide therapy in asthma: An overview.

Macrolides, a class of antimicrobials isolated from Streptomycetes more than 50 years ago, are used extensively to treat sinopulmonary infections in humans. In addition, a growing body of experimental and clinical evidence indicates that long-term (years), low (sub-antimicrobial)-dose 14- and 15-membered ring macrolide antibiotics, such as erythromycin, clarithromycin, roxithromycin and azithromycin, express immunomodulatory and tissue reparative effects that are distinct from their anti-infective properties. These salutary effects are operative in various lung disorders, including diffuse panbronchiolitis, cystic fibrosis, persistent chronic rhinosinusitis, nasal polyposis, bronchiectasis, asthma and cryptogenic organizing pneumonia.The purpose of this overview is to outline the immunomodulatory effects of macrolide antibiotics in patients with asthma.

Journal Article↗
PubMed2004

In vitro characterization of PEGylated phospholipid micelles for improved drug solubilization: effects of PEG chain length and PC incorporation.

Sterically stabilized micelles (SSM) composed of poly(ethylene glycol-2000)-grafted distearoylphosphatidylethanolamine (DSPE-PEG) and sterically stabilized mixed micelles (SSMM) composed of DSPE-PEG and egg-phosphatidyl choline (PC) have recently been introduced as novel lipid based carriers for water-insoluble drugs. However, factors that affect the solubilization behavior of these phospholipid micelles are not well understood. This study investigates the effect of PEG chain length and PC content on physical properties and solubilization potential of PEGylated phospholipid micelles. Critical micelle concentrations (CMC) determined for DSPE-PEG with different PEG chain lengths (2000, 3000, and 5000) using a fluorescent probe were in the micromolar range (0.5-1.5 microM) with higher CMC for longer PEG chain length. The size of micelles determined by quasi-elastic light scattering (QELS) showed that micellar systems became heterogeneous when PC was added at > or =25% for DSPE-PEG 2000 and > or = 40% for DSPE-PEG 5000, respectively. Above these critical PC ratios a significant increase in aggregation number and formation of rodlike particles were observed by small angle neutron scattering (SANS). Solubilization of diazepam was greater with DSPE-PEG 2000 than DSPE-PEG 5000 simple micelles as determined by RP-HPLC. However, DSPE-PEG 5000 micelles showed greater improvement in solubilization of the water-insoluble drug with an increase in PC content. In conclusion, phospholipid micelle size and solubilization potential varied with PEG chain length and PC content in the mixed micelle. Aggregation number and shape of the micelles did not significantly change until the critical PC concentrations.

Diazepam↗
PubMed2004

Helospectin I and II evoke vasodilation in the intact peripheral microcirculation.

Helospectin I and II, two closely related mammalian neuropeptides of the secretin/glucagons/vasoactive intestinal peptide (VIP) superfamily of peptides, are co-localized with VIP in nerve fibers surrounding vascular smooth muscle. However, the role if any, VIP receptors play in transducing the vasorelaxant effects of helospectin I and II in the intact peripheral microcirculation is uncertain. The purpose of this study was to determine whether helospectin I and II elicit vasodilation in the intact peripheral microcirculation and, if so, whether this response is mediated, in part, by VIP or pituitary adenylate cyclase activating peptide (PACAP) receptor engagement, and through local elaboration of cyclooxygenase products of arachidonic acid metabolism. Using intravital microscopy, we found that suffusion of helospectin I and II (each, 1.0 nmol) evoked potent vasodilation and of similar magnitude in the intact hamster cheek pouch microcirculation (P < 0.05). Suffusion of 0.1 nmol helospectin I and II had no significant effects on arteriolar diameter. Pretreatment with VIP(10-28), a VPAC1/VPAC2 receptor antagonist, or PACAP(6-38), a PAC1/VPAC2 receptor antagonist, had no significant effects on helospectin I- and II-induced responses. In addition, pretreatment with indomethacin had no significant effects on helospectin I- and II-induced vasodilation. Collectively, these data indicate that helospectin I and II evoke potent vasodilation in the intact peripheral microcirculation that is not transduced by VIP or PACAP receptors nor through cyclooxygenase products of arachidonic acid metabolism.

Animals↗
PubMed2004

Effects of peptide molecular mass and PEG chain length on the vasoreactivity of VIP and PACAP(1-38) in pegylated phospholipid micelles.

Bioactive properties of certain amphipathic peptides are amplified when self-associated with sterically stabilized micelles (SSM) composed of polyethylene glycol (PEG)-conjugated phospholipids. The purpose of this study was to determine the effects of amphipathic peptide molecular mass and PEG chain length on vasoreactivity evoked by vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, and pituitary adenylate cyclase-activating peptide(1-38) (PACAP(1-38)), a 38-amino acid neuropeptide, associated with PEGylated phospholipid micelles in vivo. Both peptides were incubated for 2 h with SSM composed of PEG with molecular mass of 2000 or 5000 grafted onto distearoyl-phosphatidylethanolamine (DSPE-PEG2000 or DSPE-PEG5000) before use. We found that regardless of peptide molecular mass, PEG chain length had no significant effects on peptide-SSM interactions. Using intravital microscopy, VIP associated with DSPE-PEG5000 SSM or DSPE-PEG2000 SSM incubated at 25 degrees C evoked similar vasodilation in the intact hamster cheek pouch microcirculation. Likewise, PACAP(1-38)-induced vasodilation was PEG chain length-independent. However, SSM-associated PACAP(1-38) evoked significantly smaller vasodilation than that evoked by SSM-associated VIP (P < 0.05) at 25 degrees C. When the incubation temperature was increased to 37 degrees C, SSM-associated PACAP(1-38)-induced vasodilation was now similar to that of SSM-associated VIP. This response was associated with a corresponding increase in alpha-helix content of both peptides in the presence of phospholipids. Collectively, these data indicate that for a larger amphipathic peptide, such as PACAP(1-38), greater kinetic energy or longer incubation period is required to optimize peptide-SSM interactions and amplify peptide bioactivity in vivo.

Animals↗
PubMed2004

Long-term montelukast therapy in moderate to severe COPD--a preliminary observation.

The purpose of this retrospective study was to determine the effects of long-term treatment with montelukast on chronic obstructive pulmonary disease (COPD) control in a cohort of patients with moderate to severe COPD. The medical records of 20 consecutive male patients (18 African-Americans) aged 71.2 +/- 10.7 years diagnosed with moderate to severe COPD at the VA Chicago Health Care System, Chicago, Illinois, USA, and treated with oral montelukast, 10 mg every night, for 23.6 +/- 7.3 months were reviewed. Information on demographics and COPD control was extracted from each record. In each patient, a comparable follow-up period in the clinic before and after initiating montelukast therapy was reviewed and tabulated so each patient served as his own control. There was a significant improvement in complaints of shortness of breath, sputum production wheezing and nocturnal symptoms during the observation period (P < 0.05). There was a significant reduction in the use of oral and inhaled corticosteroids, inhaled bronchodilators and supplemental oxygen (P < 0.05). In addition, there was a significant reduction in the number of visits to the emergency department, number of hospitalizations and duration of hospitalizations for acute exacerbations of COPD (P < 0.05). No significant changes in FEV1 (% predicted), FEV1/FVC ratio (% predicted) and peak expiratory flow rate were recorded during this time. No side effects where reported during the observation period and no patient discontinued the medication. Collectively, these data suggest that long-term treatment with montelukast is safe and improves COPD control in elderly patients with moderate to severe COPD.

Acetates↗
PubMed2004

Markers of inflammation in exhaled breath condensate of young healthy smokers.

INTRODUCTION: Although a strong correlation exists between long-term cigarette smoking, pulmonary inflammation, and COPD, efforts to identify populations at risk of acquiring COPD have so far been unsuccessful. To this end, noninvasive detection and monitoring of biomarkers of pulmonary inflammation in young healthy smokers may assist in this task. STUDY OBJECTIVES: The purpose of this study was to determine the concentrations of total protein, nitrites, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, and neutrophil chemotactic activity in exhaled breath condensate (EBC) collected from healthy college student smokers and nonsmokers. DESIGN: EBC was collected from 20 volunteers (9 nonsmokers and 11 smokers) during tidal breathing for 20 min. EBC was also collected from smokers 30 min after smoking one filtered cigarette. The concentrations of total protein, nitrite, IL-1beta, and TNF-alpha in EBC was determined by enzyme-linked immunosorbent assay. Neutrophil chemotactic activity in EBC was determined in vitro using the blind-well technique. RESULTS: The concentrations of total protein and nitrite, and neutrophil chemotactic activity were significantly higher in EBC of smokers in comparison to nonsmokers (p < 0.05). The concentrations of total protein and nitrite in the condensate of smokers did not change significantly after smoking one cigarette. The concentrations of IL-1beta and TNF-alpha in EBC were similar in nonsmokers and smokers. CONCLUSIONS: Concentrations of certain inflammatory mediators and neutrophil chemotactic activity are increased in EBC of young healthy smokers. Collection and analysis of EBC may assist in early detection of cigarette smoke-induced pulmonary inflammation and identifying populations at risk for acquiring COPD.

Adult↗
PubMed2003

VIP grafted sterically stabilized liposomes for targeted imaging of breast cancer: in vivo studies.

Targeted delivery of radionuclides and therapeutic agents to specific biomarkers of breast cancer has important implications for the diagnosis and therapy of breast cancer. Vasoactive intestinal peptide receptors (VIP-R) are approximately five times more expressed in human breast cancer, compared to normal breast tissue. We have used VIP, a 28 amino acid mammalian neuropeptide, as a breast cancer targeting moiety for targeted imaging of breast cancer. VIP was covalently attached to the surface of sterically stabilized liposomes (SSL) that encapsulated a radionuclide, Tc99m-HMPAO. Rats with n-methyl nitrosourea (MNU)-induced in situ breast cancers were used to test this targeted liposomal imaging agent. Specifically, the pharmacokinetics and biodistribution of Tc99m-HMPAO encapsulating SSL with and without VIP were determined together with their ability to image breast cancer. The presence of VIP did not alter the size and Tc99m-HMPAO encapsulation ability of SSL. It also did not alter the pharmacokinetic profile of SSL. Long-circulating liposomes with and without VIP on their surface accumulated at significantly higher quantities in breast cancer when compared to normal breast, indicating passive targeting of these constructs to cancer tissues. Importantly, in breast cancer, Tc99m-HMPAO encapsulating SSL with VIP showed significantly more accumulation than SSL without VIP. The tumor to non-tumor ratio was also significantly higher for Tc99m-HMPAO encapsulating VIP-SSL than Tc99m-HMPAO encapsulating SSL without VIP, suggesting active targeting of VIP-SSL to breast cancer. Collectively, these data showed that Tc99m-HMPAO encapsulating VIP-SSL can be successfully used for the targeted imaging of breast cancer.

Animals↗
PubMed2003

Preparation of graded materials by laterally controlled template synthesis.

A novel scheme is presented for the synthesis of graded materials by electrodeposition in porous insulating templates. Lateral control of copper electrodeposition in nanoporous alumina membranes is achieved by application of a lateral potential gradient on a thin Au film evaporated on the membrane, used as the cathode. Formation of metal gradients in the membranes is shown to occur under conditions where essentially no gradient is formed on similar bare electrodes. This is attributed to the permanent resistivity of the thin Au film between the pores, which does not disappear upon Cu deposition, allowing a potential gradient to be maintained. Formation of a copper gradient in porous alumina membranes by uniform deposition followed by gradient dissolution is also demonstrated. These results establish the feasibility of controlled electrodeposition and gradient formation in nanoporous insulating templates.

Journal Article↗
PubMed2003

Aldehydes in exhaled breath condensate of patients with chronic obstructive pulmonary disease.

The aims of the present study were (1) to evaluate whether individual aldehydes resulting from lipid peroxidation can be measured in exhaled breath condensate, (2) to assess the influence of sampling procedures on aldehyde concentrations, and (3) to compare aldehyde levels of patients with stable, moderate to severe, chronic obstructive pulmonary disease with those of smoking and nonsmoking control subjects. Aldehydes (malondialdehyde, hexanal, heptanal, and nonanal) were measured by liquid chromatography-tandem mass spectrometry in all samples and overlapping results were obtained by different sampling procedures. Malondialdehyde (57.2 +/- 2.4 nmol/L), hexanal (63.5 +/- 4.4 nmol/L), and heptanal (26.6 +/- 3.9 nmol/L) were increased in patients as compared with nonsmoking control subjects (17.7 +/- 5.5 nmol/L, p < 0.0001; 14.2 +/- 3.5 nmol/L, p = 0.004; and 18.7 +/- 0.9 nmol/L, p = 0.002, respectively). Only malondialdehyde was increased in patients compared with smoking control subjects (35.6 +/- 4.0 nmol/L, p = 0.0007). In conclusion, different classes of aldehydes were identified in exhaled breath condensate of humans. Whereas all aldehydes but nonanal were lower in control subjects as compared with other groups, only malondialdehyde distinguished smoking control subjects from patients with chronic obstructive pulmonary disease and could be envisaged as a biomarker potentially useful to monitor the disease and its response to therapy.

Adult↗
PubMed2003

Human galanin expresses amphipathic properties that modulate its vasoreactivity in vivo.

The purpose of this study was to determine whether human galanin, a pleiotropic 30-amino acid neuropeptide, expresses amphipathic properties in vitro and, if so, whether these properties modulate its vasoactive effects in the intact peripheral microcirculation. We found that human galanin aggregates in an aqueous solution and forms micelles with a critical micellar concentration (CMC) of 0.4 microM. In addition, the peptide interacted with model membrane as indicated by long and significant increase of the surface pressure of the biomimetic monolayer membrane in vitro. Interactions of human galanin with sterically stabilized phospholipid micelles (SMM) were not associated with a significant change in peptide conformation. Using intravital microscopy, we found that suffusion of human galanin alone elicited significant concentration-dependent vasoconstriction in the intact hamster cheek pouch. This response was amplified when human galanin in SSM was suffused onto the cheek pouch. The effects of human galanin alone and in SSM were mediated by galanin receptors because galantide, a galanin receptor antagonist, abrogated galanin-induced vasoconstriction. Collectively, these data show that human galanin expresses amphipathic properties in the presence of phospholipids which in turn amplifies its vasoactive effects in the intact peripheral microcirculation.

Animals↗