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Pharmaceuticals, Volume 5, Issue 5 (May 2012), Pages 405-552

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Research

Jump to: Review

Open AccessArticle Poly(ethylene glycol)-Lipid-Conjugated Antibodies Enhance Dendritic Cell Phagocytosis of Apoptotic Cancer Cells
Pharmaceuticals 2012, 5(5), 405-416; doi:10.3390/ph5050405
Received: 8 February 2012 / Revised: 27 March 2012 / Accepted: 17 April 2012 / Published: 26 April 2012
Cited by 3 | PDF Full-text (774 KB) | HTML Full-text | XML Full-text
Abstract
A simple method for attaching immunoglobulin G (IgG) on the cell surface was successfully developed for enhancing phagocytosis of apoptotic tumor cells (ATCs) by dendritic cells (DCs) ex vivo. By conjugating with a poly(ethylene glycol) (PEG)-lipid, named the biocompatible anchor for [...] Read more.
A simple method for attaching immunoglobulin G (IgG) on the cell surface was successfully developed for enhancing phagocytosis of apoptotic tumor cells (ATCs) by dendritic cells (DCs) ex vivo. By conjugating with a poly(ethylene glycol) (PEG)-lipid, named the biocompatible anchor for the membrane (BAM), arbitrary IgG could be incorporated into the cell membrane. In particular, when IgG-BAM conjugates were prepared at the optimal molar ratio of IgG to BAM (1 to 20), almost all cells were efficiently modified with IgG by treatment with IgG-BAM. This simple method was successfully applied to four types of mammalian cells. Furthermore, treatment of ATCs with the IgG-BAM conjugate increased the phagocytosis ratio of ATCs by DCs two-fold when compared to no treatment. This phagocytosis-enhancing effect was nearly identical to treatment with a tumor-specific IgG. Thus, without employing the tumor-specific IgG, which is difficult to obtain for any tumor cells and is expensive, the present method could opsonize ATC with the use of arbitrary IgG. The results strongly indicate that IgG-BAM treatment represents a promising method for opsonizing ATC with human serum IgG, and that this approach will lead to objective clinical responses in DC vaccines. Full article
(This article belongs to the Special Issue Antibody Conjugates)
Figures

Open AccessArticle The Signalling Role of the avβ5-Integrin Can Impact the Efficacy of AAV in Retinal Gene Therapy
Pharmaceuticals 2012, 5(5), 447-459; doi:10.3390/ph5050447
Received: 20 February 2012 / Revised: 3 April 2012 / Accepted: 19 April 2012 / Published: 2 May 2012
Cited by 2 | PDF Full-text (572 KB) | HTML Full-text | XML Full-text
Abstract
Sub-retinal injection of the common AAV2 pseudotypes frequently results in strong transduction of the retinal pigment epithelium (RPE) as well as the retina itself. This has been of benefit to date in human clinical trials using AAV, where the disease target is [...] Read more.
Sub-retinal injection of the common AAV2 pseudotypes frequently results in strong transduction of the retinal pigment epithelium (RPE) as well as the retina itself. This has been of benefit to date in human clinical trials using AAV, where the disease target is in the RPE. However, many mutations predisposing to retinal disease are located in the photoreceptor cells, present in the neural retina and not the RPE; in this case the sub-retinal injection route may cause an effective “loss” of therapeutic AAV to the RPE. The avβ5 integrin receptor is highly expressed on the apical surface of the RPE, and is essential to the daily phagocytosis of the outer segment tips of photoreceptor cells. The transduction efficiency of AAV was tested in the retinas of β5−/− mice lacking this receptor and showing defects in photoreceptor outer segment phagocytosis. Following sub-retinal injection of AAV2/5-eGFP, fluorescence was found to be stronger and more widespread in the neural retina of β5−/− mice compared to wild-types with greatly reduced fluorescence in the RPE. Increased levels of the phagocytic signalling protein MFG-E8, the ligand for the avβ5 integrin receptor, is found to have a moderate inhibitory effect on AAV transduction of the retina. However the opposite effect is found when only the integrin-binding domain of MFG-E8, the RGD (Arginine-Glycine-Aspartic acid) domain, was increased. In this case RGD enhanced AAV-mediated retinal transduction relative to RPE transduction. These results are presented for their relevance for the design of AAV-based retinal gene therapy strategies strategies targeting retinal/photoreceptor cells. Full article
(This article belongs to the Special Issue Gene Therapy)
Open AccessArticle Synthesis and Spectroscopic Analysis of Novel 1H-Benzo[d]imidazoles Phenyl Sulfonylpiperazines
Pharmaceuticals 2012, 5(5), 460-468; doi:10.3390/ph5050460
Received: 18 March 2012 / Revised: 18 April 2012 / Accepted: 27 April 2012 / Published: 3 May 2012
Cited by 1 | PDF Full-text (231 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
A group of benzimidazole analogs of sildenafil, 3-benzimidazolyl-4-methoxy-phenylsulfonylpiperazines 2–4 and 3-benzimidazolyl-4-methoxy-N,N-dimethyl- benzenesulfonamide (5), were efficiently synthesized. Compounds 2–5 were characterized by NMR and MS and contrary to the reported mass spectra of sildenafil, the spectra of [...] Read more.
A group of benzimidazole analogs of sildenafil, 3-benzimidazolyl-4-methoxy-phenylsulfonylpiperazines 2–4 and 3-benzimidazolyl-4-methoxy-N,N-dimethyl- benzenesulfonamide (5), were efficiently synthesized. Compounds 2–5 were characterized by NMR and MS and contrary to the reported mass spectra of sildenafil, the spectra of the piperazine-containing compounds 2–4 showed a novel fragmentation pattern leading to an m/z = 316. A mechanism for the formation of this fragment was proposed. Full article
Open AccessArticle Biochemical Traits, Survival and Biological Properties of the Probiotic Lactobacillus plantarum Grown in the Presence of Prebiotic Inulin and Pectin as Energy Source
Pharmaceuticals 2012, 5(5), 481-492; doi:10.3390/ph5050481
Received: 11 April 2012 / Revised: 9 May 2012 / Accepted: 11 May 2012 / Published: 15 May 2012
Cited by 6 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
The viability of the probiotic strain Lactobacillus plantarum subsp. plantarum, after its passage through simulated gastric and pancreatic juices, was evaluated as function of its pre-growth in a medium containing the known prebiotics pectin or inulin, and was compared to glucose [...] Read more.
The viability of the probiotic strain Lactobacillus plantarum subsp. plantarum, after its passage through simulated gastric and pancreatic juices, was evaluated as function of its pre-growth in a medium containing the known prebiotics pectin or inulin, and was compared to glucose used as control. The presence of pectin or inulin did not markedly affect the growth (10.07 log10 colony forming units/mL and 10.28 log10 colony forming units/mL for pectin and inulin respectively versus 10.42 log10 colony forming units/mL obtained for glucose). Pectin and inulin, in contrast to glucose, induced cell stress resistance against gastrointestinal juices (D log101.5 and 2.4 colony forming units/mL respectively, versus D log10 4.0 for glucose). The data were corroborated by the analysis of the protein pattern following stress treatments which, in the case of microbial cells grown with glucose, revealed a more marked protein degradation after the double passage through simulated gastric and intestinal juices. Inulin stimulated the production of the relevant healthy bio-molecule butyrate, which amount was 30% higher respect of growth in the presence of glucose. Inulin and pectin improved cell DPPH scavenging activity, and an impressive hydrophobicity (35.28% and 34.81%, respectively) was observed with respect to the microbial growth in presence of glucose (3.39%). Full article
(This article belongs to the Special Issue Probiotics and Prebiotics)

Review

Jump to: Research

Open AccessReview Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors
Pharmaceuticals 2012, 5(5), 417-446; doi:10.3390/ph5050417
Received: 3 February 2012 / Revised: 18 April 2012 / Accepted: 19 April 2012 / Published: 27 April 2012
Cited by 5 | PDF Full-text (533 KB) | HTML Full-text | XML Full-text
Abstract
G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules [...] Read more.
G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs) linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers) or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs) in pathophysiology of diseases and as the potential candidate for drug discovery. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Newer Anticoagulants for Non-Valvular Atrial Fibrillation
Pharmaceuticals 2012, 5(5), 469-480; doi:10.3390/ph5050469
Received: 29 March 2012 / Revised: 28 April 2012 / Accepted: 28 April 2012 / Published: 4 May 2012
Cited by 1 | PDF Full-text (198 KB) | HTML Full-text | XML Full-text
Abstract
Non-valvular atrial fibrillation is a recognized risk factor for stroke and systemic embolism. It has been clearly established that warfarin reduces the risk of stroke and systemic embolism in persons with atrial fibrillation and additional risk factors for stroke. The use of [...] Read more.
Non-valvular atrial fibrillation is a recognized risk factor for stroke and systemic embolism. It has been clearly established that warfarin reduces the risk of stroke and systemic embolism in persons with atrial fibrillation and additional risk factors for stroke. The use of warfarin, however, requires frequent monitoring, and there is great variability in patient response to warfarin. Warfarin interacts with several medications and foods. In addition, warfarin use portends a significant risk of bleeding. For these reasons, warfarin is frequently not prescribed to persons for whom the drug would provide a clear benefit. Over the past decade, attempts have been made to develop drugs that are at least as safe and effective as warfarin for the treatment of atrial fibrillation that do not require monitoring nor have as many interactions. Initial studies of compounds in this regard ultimately failed due to safety concerns, but over the past two years two novel agents have been approved by the United States Food and Drug Association for anticoagulation in non-valvular atrial fibrillation, another drug is under review, and additional compounds are being studied. This article will review the use of warfarin and these new agents in the treatment of non-valvular atrial fibrillation. Full article
(This article belongs to the Special Issue Anticoagulants)
Open AccessReview Selecting Molecular Recognition. What Can Existing Aptamers Tell Us about Their Inherent Recognition Capabilities and Modes of Interaction?
Pharmaceuticals 2012, 5(5), 493-513; doi:10.3390/ph5050493
Received: 5 March 2012 / Revised: 19 April 2012 / Accepted: 10 May 2012 / Published: 18 May 2012
Cited by 4 | PDF Full-text (959 KB) | HTML Full-text | XML Full-text
Abstract
The use of nucleic acid derived aptamers has rapidly expanded since the introduction of SELEX in 1990. Nucleic acid aptamers have demonstrated their ability to target a broad range of molecules in ways that rival antibodies, but advances have been very uneven [...] Read more.
The use of nucleic acid derived aptamers has rapidly expanded since the introduction of SELEX in 1990. Nucleic acid aptamers have demonstrated their ability to target a broad range of molecules in ways that rival antibodies, but advances have been very uneven for different biochemical classes of targets, and clinical applications have been slow to emerge. What sets different aptamers apart from each other and from rivaling molecular recognition platforms, specifically proteins? What advantages do aptamers as a reagent class offer, and how do the chemical properties and selection procedures of aptamers influence their function? Do the building blocks of nucleic acid aptamers dictate inherent limitations in the nature of molecular targets, and do existing aptamers give us insight in how these challenges might be overcome? This review is written as an introduction for potential endusers of aptamer technology who are evaluating the advantages of aptamers as a versatile, affordable, yet highly expandable platform to target a broad range of biological processes or interactions. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis
Pharmaceuticals 2012, 5(5), 514-528; doi:10.3390/ph5050514
Received: 5 April 2012 / Revised: 24 April 2012 / Accepted: 15 May 2012 / Published: 18 May 2012
Cited by 6 | PDF Full-text (725 KB) | HTML Full-text | XML Full-text
Abstract
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the [...] Read more.
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, FTY720-P strongly induces internalization and degradation of S1P1, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex®), S1P1 is presumed to be a useful target for the therapy of MS. Full article
(This article belongs to the Special Issue Immunosuppressant Drugs)
Open AccessReview Cannabidiol in Humans—The Quest for Therapeutic Targets
Pharmaceuticals 2012, 5(5), 529-552; doi:10.3390/ph5050529
Received: 20 April 2012 / Revised: 14 May 2012 / Accepted: 15 May 2012 / Published: 21 May 2012
Cited by 13 | PDF Full-text (306 KB) | HTML Full-text | XML Full-text
Abstract
Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim [...] Read more.
Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word “cannabidiol”. Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington’s disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed. Full article
(This article belongs to the Special Issue Medical Marijuana)

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