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Adverse hboc-endothelial dysfunction synergism: a possible
contributor to adverse clinical outcomes?
George p. Biro
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00073]
Systems Biology of HBOC-Induced Vasoconstriction
Chi-Ming Hai
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00074]
Practical Considerations In The Development Of Hemoglobin-Based
Oxygen Therapeutics
Hae Won Kim and Timothy N. Estep
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00075]
Cellular-type hemoglobin-based oxygen carrier (hemoglobin-vesicles)
as a transfusion alternative and for oxygen therapeutics
Hiromi Sakai
[Abstract] [FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00076]
Crosslinked, Polymerized, and PEG-conjugated Hemoglobin-based Oxygen Carriers: Clinical Safety and Efficacy of Recent and Current Products
Jonathan S. Jahr Arezou Sadighi Akha, Randall J. Holtby
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21745179 PubMed - indexed for MEDLINE] [BSP/CDDT/E-Pub/00078]
Long-Chain Omega-3 Fatty Acid Deficiency in Mood Disorders: Rationale for Treatment and Prevention
Robert K. McNamara
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00079]
Randomized Placebo-Controlled Trials of Omega-3 Polyunsaturated Fatty Acids in Psychiatric Disorders: a Review of Current Literature
Pierluigi Politi, Matteo Rocchetti, Enzo Emanuele, Mariangela Rondanelli and Francesco Barale
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00080]
ATP-Adenosine-Glutathione Cross-Linked Hemoglobin as Clinically Useful Oxygen Carrier
Jan Simoni, Grace Simoni, Donald E. Wesson and Mario Feola
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902624 PubMed - indexed for MEDLINE] [BSP/CDDT/E-Pub/00088]
Immunotherapy with tumor vaccines for the treatment of malignant gliomas
Divya Ajay, Luis Sanchez-Perez, Bryan D. Choi, Gabriel De Leon and John H. Sampson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00097]
Fluorescence-Guided Malignant Glioma Resections
Ranjith Babu and Cory Adamson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00098]
Targeted Radiotherapy for Malignant Gliomas
Daniel S. Oh and John P. Kirkpatrick
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00099]
Stopping Cancer in Its Tracks: Using Small Molecular Inhibitors to Target Glioblastoma Migrating Cells
Austin K. Mattox and David C. Adamson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00100]
Convection Enhanced Delivery of Macromolecules for Brain Tumors
Ankit I. Mehta, Bryan D. Choi, Divya Ajay, Raghu Raghavan, Martin Brady, Allan H. Friedman, Ira Pastan, Darell D. Bigner and John H. Sampson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00101]
Exploiting Metabolic Differences in Glioma Therapy
Francesca Galeffi and Dennis A. Turner
[Abstract] [Purchase Article] [BSP/CDDT/E-Pub/00102]
Editorial: Novel Technologies for Developing Clinically Useful Hemoglobin-Based Oxygen Carriers
Chi-Ming Hai
[BSP/CDDT/E-Pub/00103]
Microcirculation and NO-CO studies of a natural extracellular hemoglobin developed for an oxygen therapeutic carrier
Amy G. TSAI, Marcos INTAGLIETTA, Hiromi SAKAI, Eric DELPY, Christophe DRIEU LA ROCHELLE, Morgane ROUSSELOT and Franck ZAL
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00104]
QSAR and Pharmacophore Analysis of a series of Piperidinyl Urea Derivatives as hERG Blockers and H3 Antagonists
N.S. Hari Narayana Moorthy, Maria J. Ramos and Pedro A. Fernandes
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00105]
Plant bio-transformable HMG-CoA reductase gene loaded Calcium phosphate nanoparticle: In-vitro characterization and long term stability study
Mehrnaz S. Ohadi R, Amene Alvari, M. Samim and M.Z. Abdin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00106]
Chronopharmaceutics based modern colon specific drug delivery systems
Akanksha Tiwari, Raj Kumar Shukla, Suresh Tiwari and Surti Naazeen I
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00107]
Hemoglobin Encapsulated Poly(Ethylene) Glycol Surface Conjugated Vesicles Attenuates Vasoactivity Of Cell-Free Hemoglobin
Pedro Cabrales, Shahid Rameez and Andre F. Palmer
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00108]
Genotoxicity of Different Nanocarriers: Possible Modifications for the Delivery of Nucleic Acids
Vatsal Shah, Oleh Taratula, Olga B. Garbuzenko, Mahesh L. Patil, Ronak Savla, Min Zhang and Tamara Minko
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00109]
Abstracts
Adverse hboc-endothelial dysfunction synergism: a possible
contributor to adverse clinical outcomes?
George p. Biro
[FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00073]
Adverse outcomes in clinical trials on Hemoglobin Based
Oxygen Carriers (HBOCs) appear to have occurred more frequently
in HBOC treated than in control treated subjects. The differential
may be related to many factors, including study complexity
and compliance issues. Adverse outcomes also appear to be
related to chronic comorbidities in subjects undergoing elective
surgery. Frequently occurring comorbidities in these populations
are those related to aging, cardiovascular and metabolic disease
(hypertension, atherosclerosis, diabetes, etc.). These are
highly prevalent among many population subsets. These conditions
have been extensively studied and are characterized by dysfunction
of important endothelial vasoregulatory mechanisms, including
impaired nitric oxide bioavailability, excessive generation
of reactive oxygen species (ROS) and possibly enhanced vasoconstrictor
mechanisms. Although less extensively studied, HBOCs have
properties that may have an important amplifying effect upon
mechanisms operating in endothelial dysfunction, by scavenging
nitric oxide, generating further excess of ROS which in turn
react with nitric oxide, inhibit nitric oxide synthase and
possibly stimulate the release of vasoconstrictors such as
endothelin. It is likely that amplification of vasoconstrictor
effects are not uniformly operative in all vascular beds,
and that some protective autoregulatory mechanisms maintain
sufficient blood flow in vital organs as long as sufficient
vasodilator reserve is available. When the latter is exhausted
in the presence of arterial disease with physical obstructions,
blood flow to vital organs may become compromised. This paper
suggests avenues of further exploration to elucidate whether
the combination of HBOC and endothelial dysfunction is a contributing
factor in HBOC related adverse outcomes.
[Back to top]
Systems Biology of HBOC-Induced Vasoconstriction
Chi-Ming Hai
[FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00074]
Vasoconstriction is a major adverse effect of HBOCs. The
use of a single drug for attenuating HBOC-induced vasoconstriction
has been tried with limited success. Since HBOC causes disruptions
at multiple levels of organization in the vascular system,
a systems approach is helpful to explore avenues to counteract
the effects of HBOC at multiple levels by targeting multiple
sites in the system. A multi-target approach is especially
appropriate for HBOC-induced vasoconstriction, because HBOC
disrupts the cascade of amplification by NO-cGMP signaling
and protein phosphorylation, ultimately resulting in vasoconstriction.
Targeting multiple steps in the cascade may alter the overall
gain of amplification, thereby limiting the propagation of
disruptive effects through the cascade. As a result, targeting
multiple sites may accomplish a relatively high overall efficacy
at submaximal drug doses. Identifying targets and doses for
developing a multi-target combination HBOC regimen for oxygen
therapeutics requires a detailed understanding of the systems
biology and phenotypic heterogeneity of the vascular system
at multiple layers of organization, which can be accomplished
by successive iterations between experimental studies and
mathematical modeling at multiple levels of vascular systems
and organ systems. Towards this goal, this article addresses
the following topics: a) NO-scavenging by HBOC, b) HBOC autoxidation-induced
reactive oxygen species generation and endothelial barrier
dysfunction, c) NO- cGMP signaling in vascular smooth muscle
cells, d) NO and cGMP-dependent regulation of contractile
filaments in vascular smooth muscle cells, e) phenotypic heterogeneity
of vascular systems, f) systems biology as an approach to
developing a multi-target HBOC regimen.
[Back to top]
Practical Considerations In The Development Of Hemoglobin-Based
Oxygen Therapeutics
Hae Won Kim and Timothy N. Estep
[FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00075]
The development of hemoglobin based oxygen therapeutics
(HBOCs) requires consideration of a number of factors. While
the enabling technology derives from fundamental research
on protein biochemistry and biological interactions, translation
of these research insights into usable medical therapeutics
demands the application of considerable technical expertise
and consideration and reconciliation of a myriad of manufacturing,
medical, and regulatory requirements. The HBOC development
challenge is further exacerbated by the extremely high intravenous
doses required for many of the indications contemplated for
these products, which in turn implies an extremely high level
of purity is required. This communication discusses several
of the important product configuration and developmental considerations
that impact the translation of fundamental research discoveries
on HBOCs into usable medical therapeutics.
[Back to top]
Cellular-type hemoglobin-based oxygen carrier (hemoglobin-vesicles)
as a transfusion alternative and for oxygen therapeutics
Hiromi Sakai
[FULL-TEXT
INQUIRY] [BSP/CDDT/E-Pub/00076]
Many researchers have tested a hemoglobin (Hb) solution as
a possible oxygen carrier after discovering that one Hb molecule
contains four hemes that bind and release oxygen reversibly,
and that blood type antigens are expressed on the surface
of red blood cells (RBCs). However, various side effects emerged
during the long development of Hb-based oxygen carriers (HBOCs).
The physiological significance of the RBC structure is undergoing
reconsideration. Fundamentally, excessive native Hb molecules
are toxic, but encapsulation can shield this toxic effect.
So-called liposome-encapsulated Hb or Hb-vesicles that mimic
the cellular structure of RBCs have been developed for clinical
applications.
[Back to top]
Crosslinked, Polymerized, and PEG-conjugated Hemoglobin-based Oxygen Carriers: Clinical Safety and Efficacy of Recent and Current Products
Jonathan S. Jahr Arezou Sadighi Akha, Randall J. Holtby
[FULL-TEXT INQUIRY] [PMID: 21745179 PubMed - indexed for MEDLINE] [BSP/CDDT/E-Pub/00078]
Blood substitutes, especially hemoglobin based oxygen carriers (HBOC) have been widely studied and reviewed over the past 30 years. The development of HBOCs was highlighted by crosslinking to minimize adverse effects. However, even early attempts at single crosslinking using alpha-alpha crosslinks or diaspirin crosslinking failed clinical trials due to renal morbidity and increased mortality. In fact, preclinical trials may have predicted failure of this first generation product, DCLHb (diaspirin-crosslinked Hb) (HemAssist ®, Baxter). In the 1980's, three small biopharmaceutical companies developed "second generation" HBOCs, the first being Hemosol with their raffinose crosslinked HBOC, hemoglobin-raffimer. The other two development programs modified the HBOC using glutaraldehyde polymerization, in an attempt to further alleviate the toxicities of the "first" generation HBOCs. This paper will review the definitive clinical trials of the two polymerized HBOCs, Biopure's hemoglobin glutamer-250 (bovine) and Northfield's polymerized human Hb, pegylated HBOC and Sangart's peg-conjugated HBOC, with an introductory brief review of Hemosol's hemoglobin-raffimer. The paper will then introduce the newest polymerized hemoglobin, zero-linked hemoglobin polymer, which has not yet undergone clinical trials but has undergone some preclinical work that will be discussed in a section on this product. As a new generation HBOC, zero-linked hemoglobin polymer may begin to address the issues presented by the first two generations of HBOCs, and may hold promise as a universally applicable HBOC.
[Back to top]
Long-Chain Omega-3 Fatty Acid Deficiency in Mood Disorders: Rationale for Treatment and Prevention
Robert K. McNamara
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00079]
Major recurrent mood disorders including major depressive disorder (MDD) and bipolar disorder (BD) are associated with significant psychosocial morbidity and excess premature mortality primarily attributable to suicide and coronary heart disease. Limited efficacy and adverse side-effects associated with psychotropic medications used in the treatment of MDD and BD highlight the urgent need to develop safe and efficacious treatments or treatment adjuncts. A body of evidence now indicates that long-chain omega-3 (LCn-3) fatty acid deficiency is a feature associated with MDD and BD. The etiology of LCn-3 deficits in MDD and BD patients may be attributable to both genetic and environmental factors. Dietary LCn-3 supplementation is safe and well-tolerated with chronic administration and corrects LCn-3 deficiency in MDD and BD patients. LCn-3 supplementation has been found to augment the therapeutic efficacy of psychotropic medications in the treatment of mood symptoms and to reduce suicidality. Preliminary studies also suggest that LCn-3 supplementation is efficacious as monotherapy in the treatment and prevention of psychopathology in children and adolescents. LCn-3 supplementation may also be associated with reduced risk for developing coronary heart disease. The overall cost-benefit ratio associated with LCn-3 supplementation provides a strong rationale to diagnose and treat LCn-3 deficiency in MDD and BD patients, and to prevent LCn-3 deficiency in subjects at high risk for developing these disorders.
[Back to top]
Randomized Placebo-Controlled Trials of Omega-3 Polyunsaturated Fatty Acids in Psychiatric Disorders: a Review of Current Literature
Pierluigi Politi, Matteo Rocchetti, Enzo Emanuele, Mariangela Rondanelli and Francesco Barale
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00080]
Growing evidence suggests the clinical usefulness of omega (ω)-3 polyunsaturated fatty acids (PUFA) in patients with psychiatric disorders. In the present review, we summarize the findings of randomized placebo-controlled clinical trials focusing on the potential therapeutic utility of omega-3 PUFA in mental illnesses. We searched the Pubmed databese for placebo-controlled clinical trials utilizing the keywords PUFA, omega 3, eicosapentaenoic acid, docosahexaenoic acid in combination with the following terms: anxiety disorders, autism, attention-deficit hyperactivity disorder (ADHD), personality disorders, and schizophrenia. The literature review indicated that personality disorders, autism, and anxiety disorders have been less investigated than mood disorder, schizophrenia, and ADHD. While no definite conclusions can be drawn on the therapeutic efficacy of ω-3 PUFA in the majority of psychiatric illnesses examined herein, evidence suggests the potential preventive role of this molecules in subjects at ultra-high risk for developing psychosis. Hopefully, future studies in the field should examine the turnover of ω-PUFA in the neural membranes. Moreover, special attention should be paid to potential confounders such as dietary or smoking habits.
[Back to top]
ATP-Adenosine-Glutathione Cross-Linked Hemoglobin as Clinically Useful Oxygen Carrier
Jan Simoni, Grace Simoni, Donald E. Wesson and Mario Feola
[FULL-TEXT INQUIRY] [PMID: 21902624 PubMed - indexed for MEDLINE] [BSP/CDDT/E-Pub/00088]
To attenuate hemoglobin’s (Hb) intrinsic toxicity, Texas Tech University scientists developed a novel concept of “pharmacologic cross-linking” to formulate an effective oxygen carrier, HemoTech, which consists of purified bovine Hb cross-linked intramolecularly with ATP and intermolecularly with adenosine, and conjugated with reduced glutathione (GSH). In this composition, while ATP prevents Hb dimerization, adenosine permits the formation of homogeneous polymers. ATP also serves as a regulator of blood vessel tone via activation of the P2Y receptor, whereas adenosine counteracts the vasoconstrictive and pro-inflammatory properties of Hb via stimulation of adenosine A2 and A3 receptors. GSH introduces electronegative charge onto the Hb surface that blocks Hb’s transglomerular and transendothelial passage. Besides, GSH shields heme from nitric oxide and reactive oxygen species, thus enhancing vasodilation and lowering Hb pro-oxidative potential. HemoTech underwent favorable initial pre-clinical testing and proof of medical concept, and is under commercial development by HemoBioTech Inc. HemoTech has entered the regulatory process in the US. Several mandated requirements have already been met, including viral/transmissible spongiform encephalopathy (TSE) clearance validation studies and various pre-clinical pharmacological, pharmacokinetic, toxicological, genotoxicity and efficacy tests. These studies provided further evidence that “pharmacologic cross-linking” of the Hb molecule with ATP, adenosine and GSH, is useful for designing a viable Hb-based oxygen carrier.
[Back to top]
Immunotherapy with tumor vaccines for the treatment of malignant gliomas
Divya Ajay, Luis Sanchez-Perez, Bryan D. Choi, Gabriel De Leon and John H. Sampson
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00097]
With an average life expectancy of 14 months, Glioblastoma multiforme (GBM), is the most aggressive primary brain tumor. Our growing understanding of the immune system and its role in oncogenesis has helped develop cancer vaccines as a promising treatment modality against this disease. What follows is a comprehensive discussion on the history of immunotherapy and the various vaccine based therapies being developed and utilized for the treatment of malignant gliomas.
[Back to top]
Fluorescence-Guided Malignant Glioma Resections
Ranjith Babu and Cory Adamson
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00098]
Gliomas are the most common primary brain tumors and result in dismal outcomes when present at high grades. Surgery is the first-line treatment, and maximum safe resection is recommended. However, the infiltrative nature of malignant gliomas makes complete resection difficult as tumor margins are unclear. The use of fluorescence to delineate tumor margins intraoperatively has emerged as a safe and effective tool for increasing the extent of resection. This review discusses several exogenous agents that have been investigated in humans. Aminolevulinic acid is the most studied fluorophore and has been used in many clinical trials, including a multi-center phase III randomized controlled trial. It has been shown to increase extent of resection, progression-free survival, and overall survival. Another fluorophore, fluorescein, has also demonstrated utility in increasing resection quality and overall survival. Developing technologies such as fluorescence spectroscopy to enhance endogenous fluorescence has fairly recently been shown to delineate tumor margins intraoperatively. This method does not require the administration of exogenous agents, but instead distinguishes tumor from normal brain by using changes in the fluorescence emission profile of the tissue. This review also discusses various agents such as nanoparticles that are currently in preclinical testing. Fluorescence-guided resections show great promise for furthering our surgical abilities, and in the foreseeable future will become the standard of care for patients diagnosed with gliomas.
[Back to top]
Targeted Radiotherapy for Malignant Gliomas
Daniel S. Oh and John P. Kirkpatrick
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00099]
Malignant glioma remains a disease with poor prognosis despite recent advances in the multidisciplinary care of this disease. Herein we review the evolution of and recent advances in radiation therapy for malignant glioma that have allowed for more targeted therapy, potentially improving efficacy while decreasing normal tissue toxicity. Current and emerging techniques are presented, including stereotactic radiotherapy and radiosurgery, brachytherapy, radioimmunotherapy, and charged particle therapy, as well as the combination of these modalities with novel targeted biochemotherapies.
[Back to top]
Stopping Cancer in Its Tracks: Using Small Molecular Inhibitors to Target Glioblastoma Migrating Cells
Austin K. Mattox and David C. Adamson
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00100]
Glioblastoma multiforme (GBM) represents one of the most common aggressive types of primary brain tumors. Despite advances in surgical resection, novel neuroimaging procedures, and the most recent adjuvant radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Targeting migrating GBM cells is a key research strategy in the fight against this devastating cancer. Though the vast majority of the primary tumor focus can be surgically resected, these migrating cells are responsible for its universal recurrence. Numerous strategies and technologies are being explored to target migrating glioma cells, with small molecular inhibitors as one of the most commonly studied. Small molecule inhibitors, such as protein kinase inhibitors, phosphorylation site inhibitors, protease inhibitors, and anti-sense oligonucleotides show promise in slowing the progression of this disease. A better understanding of these small molecule inhibitors and how they target various extra- and intracellular signaling pathways may eventually lead to a cure for GBM.
[Back to top]
Convection Enhanced Delivery of Macromolecules for Brain Tumors
Ankit I. Mehta, Bryan D. Choi, Divya Ajay, Raghu Raghavan, Martin Brady, Allan H. Friedman, Ira Pastan, Darell D. Bigner and John H. Sampson
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00101]
The blood brain barrier (BBB) poses a significant challenge for drug delivery of macromolecules into the brain. Convection-enhanced delivery (CED) circumvents the BBB through direct intracerebral infusion using a hydrostatic pressure gradient to transfer therapeutic compounds. The efficacy of CED is dependent on the distribution of the therapeutic agent to the targeted region. Here we present a review of convection enhanced delivery of macromolecules, emphasizing the role of tracers in enabling effective delivery anddiscuss current challenges in the field.
[Back to top]
Exploiting Metabolic Differences in Glioma Therapy
Francesca Galeffi and Dennis A. Turner
[Purchase Article] [BSP/CDDT/E-Pub/00102]
Brain function depends upon complex metabolic interactions amongst only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolysis and metabolism associated with synthesis of critical intermediates, hence are less susceptible to lack of oxygen. Astrocytoma and higher grade glioma cells demonstrate both basic metabolic mechanisms of astrocytes as well as tumors in general, e.g. they show a high glycolytic rate, lactate extrusion, ability to proliferate even under hypoxia, and opportunistic use of mechanisms to enhance metabolism and blood vessel generation, and suppression of cell death pathways. There may be differences in metabolism between neurons, normal astrocytes and astrocytoma cells, providing therapeutic opportunities against astrocytomas, including a wide range of enzyme and transporter differences, regulation of hypoxia-inducible factor (HIF), glutamate uptake transporters and glutamine utilization, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of NADPH for lipid synthesis, utilizing differential regulation of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate dehydrogenase, lactate dehydrogenase, malate-aspartate NADH shuttle) and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone, and are starting to be implemented in clinical trials.
[Back to top]
Editorial: Novel Technologies for Developing Clinically Useful Hemoglobin-Based Oxygen Carriers
Chi-Ming Hai
[BSP/CDDT/E-Pub/00103]
Blood is essential to life, but is often in short supply in major catastrophes. Since hemoglobin within erythrocytes is the major oxygen carrier in blood, the development of artificial hemoglobin-based oxygen carriers (HBOCs) for oxygen therapeutics has captured the imagination and dedication of many scientists and technologists for over 30 years. At the present time, adverse effects of HBOCs remain a major barrier to FDA approval for clinical application; however, the following reasons suggest hope. First, major adverse effects of HBOCs and the underlying mechanisms have largely been identified. Second, multiple HBOCs of different designs for addressing the adverse effects of HBOCs have been developed. Therefore, it seems promising that coordinated and collaborative research and development among HBOC scientists and technologists may lead to the development of a clinically useful HBOC. Towards this goal, this special issue serves as a common forum for presenting the latest technologies for developing clinically useful HBOCs. These technologies include polymerizing hemoglobin in vitro or extracting naturally polymerized hemoglobin from marine animals, cross-linking hemoglobin with polyethylene glycol, ATP-adenosine-glutathione, or antioxidant enzyme, and encapsulating hemoglobin with phospholipid or polymer. In addition, one article addresses adverse HBOC-endothelial dysfunction synergism as a possible contributor to adverse clinical outcomes, whereas another article introduces systems biology as a discipline for gaining a systems-level mechanistic understanding HBOC-induced vasoconstriction. Finally, one article outlines practical considerations in the development of hemoglobin-based oxygen therapeutics. We hope that this special issue contributes to the development of oxygen carriers that may eventually gain approval for clinical use in the near future.
[Back to top]
Microcirculation and NO-CO studies of a natural extracellular hemoglobin developed for an oxygen therapeutic carrier
Amy G. TSAI, Marcos INTAGLIETTA, Hiromi SAKAI, Eric DELPY, Christophe DRIEU LA ROCHELLE, Morgane ROUSSELOT and Franck ZAL
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00104]
Extracellular soluble hemoglobins (Hbs) have long been studied for their possible use as safe and effective alternatives to blood transfusion. While remarkable progress has been made in the use of cell-free Hb as artificial oxygen carrier, significant problems remain, including susceptibility to oxidative inactivation and propensity to induce vasoconstriction. Hemarina-M101 is a natural giant extracellular hemoglobin (3600 kDa) derived from marine invertebrate (polychaete annelid). Hemarina-M101 is a biopolymer composed of 156 globins and 44 non-globin linker chains and formulated in a product called HEMOXYCarrier®. Prior work has shown Hemarina-M101 to possess unique anti-oxidant activity and a high oxygen affinity. Topload experiment with this product into rats did not revealed any effect on heart rate and mean arterial pressure (MAP). A pilot study with the hamster dorsal skinfold window chamber model showed absence of microvascular vasoconstriction and no significant impact on mean arterial blood pressure. In vitro nitric oxide (NO) and carbon monoxide (CO) reaction kinetics measurements show that Hemarina-M101 has different binding rates as compared to human Hb. These results revealed for the first time that the presence of this marine hemoglobin appears to have no vasoactivity at the microvascular level in comparison to others HBOC developed so fare and merits further investigation.
[Back to top]
QSAR and Pharmacophore Analysis of a series of Piperidinyl Urea Derivatives as hERG Blockers and H3 Antagonists
N.S. Hari Narayana Moorthy, Maria J. Ramos and Pedro A. Fernandes
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00105]
In the present study, a computational based pharmacophore and structural analysis were performed on a series of piperidinyl urea derivatives, a limited number of compounds which have variation in structure and activities that exhibit hERG blocking and H3 antagonistic activities. The conducted QSAR studies demonstrated that the developed models are statistically significant, which have been confirmed through validation. The Q2 values for the models developed with hERG blocking activity are >0.8 and with the H3 antagonistic activity are >0.6. The descriptors contributed in the models show that the distributed polar properties on the vdW surface of the molecules are important for the hERG blocking activity. The vsurf_ descriptors (surface area, volume and shape) such as vsurf_DD13 and vsurf_Wp4 correlate with the H3 antagonistic activity of these compounds. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), hydrophobic (hyd) and aromatic/hydrophobic (aro/hyd) pharmacophore properties are favorable contours sites for both the activities. Also, our study reveals that the distance between the polar contours (acc, don, etc) has to be small for better hERG blocking activity. The distances between the aro/hyd to the polar groups should be higher for better hERG blocking activity. However, the H3 antagonistic activity for these series depends upon hydrophobic property of the molecules, particularly the hyd and the hyd/aro contours of the molecules. Hence, these results reveal the requirements on the structural properties and the distances between the pharmacophore contour sites of the molecules responsible for their hERG and H3 antagonistic activities.
[Back to top]
Plant bio-transformable HMG-CoA reductase gene loaded Calcium phosphate nanoparticle: In-vitro characterization and long term stability study
Mehrnaz S. Ohadi R, Amene Alvari, M. Samim and M.Z. Abdin
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00106]
Encapsulation of plasmid DNA (pDNA) in nanoparticle is expected to enhance the stability of DNA, reproducibility and frequency of the genetic transformation in plants. Here we report the development and characterization of HMG Co-A reductase gene loaded biocompatible calcium phosphate nanoparticles. The synthesis of nanoparticles was confirmed by DSC, FT-IR, and XRD. The spherical nanoparticles were shown to have the particle size and zeta potential varied from 10.86±0.09nm to 33.42±0.18nm and -25.5±0.07mV to -31.7±0.07mV for Cap-I to Cap-IV. DNA releasing experiments showed that in acidic media, initially slow release followed by fast release with a maximum release of Cap-I (95.77±1.39%)> Cap-II (87.32±2.07%)> Cap-III (76.54±2.01%)> Cap-IV (72.93±1.75%) over 60min. However, in alkaline pH, the chemical breakdown of matrix was very slow and the maximum release of pDNA was 5.91±0.90% in 60 minutes. Compared to wild type C. intybus, transformation efficiency and enhanced biosynthesis of esculin with the DNA nanoparticles in C. intybus were about 10% and 71%, respectively.
Cap nanoparticles were quite stable at 40±0.5°C/75±5%RH, 25±0.5°C/60±RH, 4±0.5°C/ambient humidity and the integrity of pDNA encapsulated was confirmed by gel electrophoresis. Furthermore, the biotransformed plants show relatively high antioxidant activity capacity, possibly due to high accumulation of esculin. Transformation efficiency and enhanced biosynthesis of esculin with Cap nanoparticle in C. intybus were 9.62% and 70.87% (compared to wild type C. intybus), respectively. Antioxidant activity capacity of the biotransformed plants was significantly higher than the normal plant due to high accumulation of esculin.
[Back to top]
Chronopharmaceutics based modern colon specific drug delivery systems
Akanksha Tiwari, Raj Kumar Shukla, Suresh Tiwari and Surti Naazeen I
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00107]
Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. The advancement in the field of chronobiology, modern drug delivery approaches have been elevated to a new concept of chronopharmacology i.e. the ability to deliver the therapeutic agent to a patient in a staggered profile. The increasing research interest surrounding this delivery system has widened the areas of pharmaceutics in particular with many more sub-disciplines expected to coexist in the near future. Chronopharmaceutics based technology has eliminated the drawbacks associated with the conventional colon specific delivery systems. This review on chronopharmaceutics based delivery gives a comprehensive emphasis on the existing technologies and future development.
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Hemoglobin Encapsulated Poly(Ethylene) Glycol Surface Conjugated Vesicles Attenuates Vasoactivity Of Cell-Free Hemoglobin
Pedro Cabrales, Shahid Rameez and Andre F. Palmer
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00108]
Widespread clinical use of acellular hemoglobin (Hb)-based O2 carriers (HBOCs) has been hampered by their ability to elicit both vasoconstriction and systemic hypertension. This is primarily due to the ability of acellular Hb to extravasate through the blood vessel wall and scavenge endothelial-derived nitric oxide (NO). Encapsulation of Hb inside the aqueous core of liposomes retards the rates of NO dioxygenation and O2 release, which should reduce or eliminate the vasoactivity of Hb. Our aim is to determine the extent of systemic and microvascular vasoactive responses (hypertension, vasoconstriction and hypoperfusion) after infusion of vesicle encapsulated Hbs, in which the encapsulated Hb is in either the deoxygenated or carbon monoxide (CO) state (HbV and COHbV, respectively). To investigate this hypothesis, we used the hamster window chamber model subjected to two successive hypervolemic infusions of HbV and COHbV solutions (each infusion represents 10% of the animal’s calculated blood volume) at Hb concentrations of either 7 or 10 g/dL. The hypervolemic infusion model used in this study has all the regulatory mechanisms responsible for predicting the vasoconstrictive responses of HBOCs. The results of this study demonstrate the absence of vasoconstrictive and hypertensive responses upon single and multiple infusions of HbV and COHbV solutions. The HbV and COHbV solutions increased the plasma O2 carrying capacity. However, COHbV delivered low therapeutic levels of CO without inducing any microcirculatory disturbances. Significance: Vesicles containing Hb can be used as a new therapeutic agent in transfusion medicine to treat anemia and revert hypoperfusion.
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Genotoxicity of Different Nanocarriers: Possible Modifications for the Delivery of Nucleic Acids
Vatsal Shah, Oleh Taratula, Olga B. Garbuzenko, Mahesh L. Patil, Ronak Savla, Min Zhang and Tamara Minko
[FULL-TEXT INQUIRY] [BSP/CDDT/E-Pub/00109]
The prevention of cyto- and genotoxicity of nanocarriers is an important task in nanomedicine. In the present investigation, we, at the first time using similar experimental conditions, compared genotoxicity of nanocarriers with different composition, architecture, size, molecular weight and charge. Poly(ethylene glycol) polymers, neutral and cationic liposomes, micelles, poly(amindo amine) and poly(propyleneimine) dendrimers, quantum dots, mesoporous silica, and supermagnetic iron oxide (SPIO) nanoparticles were studied. All nanoparticles were used in non-cytotoxic concentrations. However, even in these concentrations, positively charged cationic liposomes, dendrimers, and SPIO nanoparticles induced genotoxicity leading to the significant formation of micronuclei in cells. Negatively charged and neutral nanocarriers were not genotoxic. A strong positive correlation was found between the number of formed micronuclei and the positive charge of nanocarriers. We proposed modifications of both types of dendrimers and SPIO nanoparticles that substantially decreased their genotoxicity and allowed for an efficient intracellular delivery of nucleic acids.
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