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Systemic Delivery (systemic + delivery)
Selected Abstracts3352: The effects of high altitude on central corneal thicknessACTA OPHTHALMOLOGICA, Issue 2010H BASMAK Purpose A large number of people are exposed to long-term hypobaric hypoxic conditions via mountaineering, skiing and trekking. Other people such as aviators and high-altitude parachutists are exposed to short-term hypobaric hypoxic conditions. It is known that hypobaric conditions alter physiological and morphological status of the eye including the central corneal thickness (CCT). Our aim is to review the results of the influences of high altitude on CCT. We will also add our experience on the influences of short-term hypobaric hypoxia on CCT. Methods Reports covering this topic will be discussed. The possible mechanisms for the alterations in CCT will be included. Hypobaric hypoxic conditions simulate high altitudinal environments, which was the basis of our study covering 70 eyes of 35 healthy men exposed to hypobaric hypoxic condition. We measured the CCT via ultrasound pachmetry at local ground (792 m above sea level) and then during short-term hypobaric hypoxic exposure (equivalent 9144 m above). Results CCT has been found to be increased at high altitudes. We also found that hypobaric hypoxic condition increased the CCT significantly. The mechanism of increased CCT is not clear, although the alterations in corneal endothelial cells function seem to be the main explanation. Systemic delivery of oxygen to the anterior chamber can possibly be an important contributing factor based on a recent study. Conclusion CCT has been reported to be increased at high altitude. The possible underlying mechanisms are altered endothelial function and metabolic activity. [source] Antisense applications for biological controlJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Wei-Hua Pan Abstract Although Nature's antisense approaches are clearly impressive, this Perspectives article focuses on the experimental uses of antisense reagents (ASRs) for control of biological processes. ASRs comprise antisense oligonucleotides (ASOs), and their catalytically active counterparts ribozymes and DNAzymes, as well as small interfering RNAs (siRNAs). ASOs and ribozymes/DNAzymes target RNA molecules on the basis of Watson-Crick base pairing in sequence-specific manner. ASOs generally result in destruction of the target RNA by RNase-H mediated mechanisms, although they may also sterically block translation, also resulting in loss of protein production. Ribozymes and DNAzymes cleave target RNAs after base pairing via their antisense flanking arms. siRNAs, which contain both sense and antisense regions from a target RNA, can mediate target RNA destruction via RNAi and the RISC, although they can also function at the transcriptional level. A considerable number of ASRs (mostly ASOs) have progressed into clinical trials, although most have relatively long histories in Phase I/II settings. Clinical trial results are surprisingly difficult to find, although few ASRs appear to have yet established efficacy in Phase III levels. Evolution of ASRs has included: (a) Modifications to ASOs to render them nuclease resistant, with analogous modifications to siRNAs being developed; and (b) Development of strategies to select optimal sites for targeting. Perhaps the biggest barrier to effective therapies with ASRs is the "Delivery Problem." Various liposomal vehicles have been used for systemic delivery with some success, and recent modifications appear to enhance systemic delivery, at least to liver. Various nanoparticle formulations are now being developed which may also enhance delivery. Going forward, topical applications of ASRs would seem to have the best chances for success. In summary, modifications to ASRs to enhance stability, improve targeting, and incremental improvements in delivery vehicles continue to make ASRs attractive as molecular therapeutics, but their advance toward the bedside has been agonizingly slow. J. Cell. Biochem. 98: 14,35, 2006. © 2006 Wiley-Liss, Inc. [source] Relative roles of TGF-,1 and Wnt in the systemic regulation and aging of satellite cell responsesAGING CELL, Issue 6 2009Morgan E. Carlson Summary Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged P-Smad3, differentiated niche, and by the aged circulation. With respect to muscle fibers, we previously established that a shift from active Notch to excessive transforming growth factor-beta (TGF-,) induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses. In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt. Here, we examined the age-dependent myogenic activity of sera TGF-,1, and its potential cross-talk with systemic Wnt. We found that sera TGF-,1 becomes elevated within aged humans and mice, while systemic Wnt remained undetectable in these species. Wnt also failed to inhibit satellite cell myogenicity, while TGF-,1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-,1 were inhibitory and young sera suppressed myogenesis if TGF-,1 was activated. Our data suggest that platelet-derived sera TGF-,1 levels, or endocrine TGF-,1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-, neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-,1 and rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-, receptor kinase inhibitor, which attenuated TGF-, signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-,1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-,1, and introduce new therapeutic strategies for the broad restoration of aged organ repair. [source] Non-invasive systemic drug delivery: Developability considerations for alternate routes of administrationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010Neil R. Mathias Abstract Over the past few decades alternate routes of administration have gained significant momentum and attention, to complement approved drug products, or enable those that cannot be delivered by the oral or parenteral route. Intranasal, buccal/sublingual, pulmonary, and transdermal routes being the most promising non-invasive systemic delivery options. Considering alternate routes of administration early in the development process may be useful to enable new molecular entities (NME) that have deficiencies (extensive first-pass metabolism, unfavorable physicochemical properties, gastro-intestinal adverse effects) or suboptimal pharmacokinetic profiles that are identified in preclinical studies. This review article describes the various delivery considerations and extraneous factors in developing a strategy to pursue an alternate route of administration for systemic delivery. The various delivery route options are outlined with their pros and cons; key criteria and physicochemical attributes that would make a drug a suitable candidate are discussed; approaches to assess delivery feasibility, toxicity at the site of delivery, and overall developability potential are described; and lastly, product trends and their disease implications are highlighted to underscore treatment precedence that help to build scientific rationale for the pursuit of an alternate route of administration. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1,20, 2010 [source] Effect of dimethyl-,-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008Monireh Jalalipour Abstract The aim of this article is to prepare and characterize inhalable dry powders of recombinant human growth hormone (rhGH), and assess their efficacy for systemic delivery of the protein in rats. The powders were prepared by spray drying using dimethyl-,-cyclodextrin (DM,CD) at different molar ratios in the initial feeds. Size exclusive chromatography was performed in order to determine protecting effect of DM,CD on the rhGH aggregation during spray drying. By increasing the concentration of DM,CD, rhGH aggregation was decreased from 9.67 (in the absence of DM,CD) to 0.84% (using DM,CD at 1000 molar ratio in the spray solution). The aerosol performance of the spray dried (SD) powders was evaluated using Andersen cascade impactor. Fine particle fraction values of 53.49%, 33.40%, and 23.23% were obtained using DM,CD at 10, 100, and 1000 molar ratio, respectively. In vivo studies showed the absolute bioavailability of 25.38%, 76.52%, and 63.97% after intratracheal insufflation of the powders produced after spray drying of the solutions containing DM,CD at 10, 100, and 1000 molar ratio, respectively in rat. In conclusion, appropriate cyclodextrin concentration was achieved considering the protein aggregation and aerosol performance of the SD powders and the systemic absorption following administration through the rat lung. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5176,5185, 2008 [source] Photodynamic therapy: update 2006 Part 1: Photochemistry and photobiologyJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 3 2007PG Calzavara-Pinton Abstract Photodynamic therapy (PDT) is a two-step therapeutic technique in which the topical or systemic delivery of photosensitizing drugs is followed by irradiation with visible light. Activated photosensitizers transfer energy to molecular oxygen, generating reactive oxygen species (ROS). The subsequent oxidation of lipids, amino acids and proteins induces cell necrosis and apoptosis. In addition, ROS indirectly stimulate the transcription and release of inflammatory mediators. The photosensitizers are selective, in that they penetrate and accumulate in tumour cells or in the endothelium of newly formed vessels while generally avoiding the surrounding healthy tissue. The mechanisms of penetration through the cell membrane and the pattern of subcellular localization strongly influence the type of cellular effect. The photobiology and photoimmunology of the haematoporphyrin (Hp) derivative and its purified, lyophilized and concentrated form porfimer sodium have been investigated over the past 30 years. However, interest in PDT in dermatology was not raised until the 1990s with the availability of a simple and effective technique, the topical application of aminolaevulinic acid (ALA) and its methyl ester (methyl aminolaevulinate, MAL) followed by irradiation with broadband red light. At the same time, several new ,second-generation' synthetic sensitizers (e.g. benzoporphyrin derivatives, phthalocyanines, chlorins and porphycenes) became available. These compounds are chemically pure, highly efficient, selective and safe, while offering the advantage that the generalized skin photosensitivity they produce lasts for only a short time. They are currently under clinical evaluation but have not yet been approved for clinical use. This paper provides an overview of the chemistry of the photosensitizers, the photobiology and photoimmunology of the photodynamic reaction as well as the photophysical characteristics of the light sources available for PDT. [source] Sustained delivery of therapeutic concentrations of human clotting factor IX , a comparison of adenoviral and AAV vectors administered in uteroTHE JOURNAL OF GENE MEDICINE, Issue 1 2002Holm Schneider Abstract Background Prenatal somatic gene therapy has been considered for genetic disorders presenting with morbidity at birth. Haemophilia is associated with an increased risk of catastrophic perinatal bleeding complications such as intracranial haemorrhage, which could be prevented by gene transfer in utero. Prenatal gene therapy may be more promising than postnatal treatment, as the fetus may be more amenable to uptake and integration of therapeutic DNA and the immaturity of its immune system may permit life-long immune tolerance of the transgenic protein, thus avoiding the dominant problem in haemophilia treatment, the formation of inhibitory antibodies. Methods Adenovirus serotype 5-derived or AAV serotype 2-derived vectors carrying human clotting factor IX (hfIX) cDNA or a reporter gene were administered intramuscularly, intraperitoneally or intravascularly to late-gestation mouse fetuses. Both vector types were evaluated with respect to the kinetics of hfIX delivery to the systemic circulation and possible immune responses against the vector or the transgene product. Results Mice treated in utero by intramuscular injection of an adenoviral vector carrying hfIX cDNA exhibited high-level gene expression at birth and therapeutic , albeit continuously decreasing , plasma concentrations of hfIX over the entire 6 months of the study. Adenoviral vector spread to multiple organs was detected by polymerase chain reaction (PCR). Intramuscular, intraperitoneal or intravascular application of AAV vectors carrying hfIX cDNA led to much lower plasma concentrations of hfIX shortly after birth, which appeared to decline during the first month of life but stabilized in some of the mice at detectable levels. No signs of immune responses were found, either against the different viral vectors or against hfIX. Conclusion This study demonstrates for the first time that sustained systemic delivery of a therapeutic protein can be achieved by prenatal gene transfer. It thus shows the feasibility of gene therapy in utero and provides a basis for considering this concept as a preventive therapeutic strategy for haemophilia and perhaps also for other plasma protein deficiencies. Copyright © 2002 John Wiley & Sons, Ltd. [source] A Synthetic Mechano Growth Factor E Peptide Enhances Myogenic Precursor Cell Transplantation SuccessAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2007P. Mills Myogenic precursor cell (MPC) transplantation is a good strategy to introduce dystrophin expression in muscles of Duchenne muscular dystrophy (DMD) patients. Insulin-like growth factor (IGF-1) promotes MPC activities, such as survival, proliferation, migration and differentiation, which could enhance the success of their transplantation. Alternative splicing of the IGF-1 mRNA produces different muscle isoforms. The mechano growth factor (MGF) is an isoform, especially expressed after a mechanical stress. A 24 amino acids peptide corresponding to the C-terminal part of the MGF E domain (MGF-Ct24E peptide) was synthesized. This peptide had been shown to enhance the proliferation and delay the terminal differentiation of C2C12 myoblasts. The present study showed that the MGF-Ct24E peptide improved human MPC transplantation by modulating their proliferation and differentiation. Indeed, intramuscular or systemic delivery of this synthetic peptide significantly promoted engraftment of human MPCs in mice. In vitro experiments demonstrated that the MGF-Ct24E peptide enhanced MPC proliferation by a different mechanism than the binding to the IGF-1 receptor. Moreover, MGF-Ct24E peptide delayed human MPC differentiation while having no outcome on survival. Those combined effects are probably responsible for the enhanced transplantation success. Thus, the MGF-Ct24E peptide is an interesting agent to increase MPC transplantation success in DMD patients. [source] Endothelial progenitor cell transplantation improves long-term stroke outcome in miceANNALS OF NEUROLOGY, Issue 4 2010Yongfeng Fan PhD Objective Endothelial progenitor cells (EPCs) play an important role in tissue repairing and regeneration in ischemic organs, including the brain. However, the cause of EPC migration and the function of EPCs after ischemia are unclear. In this study, we demonstrated the effects of EPCs on ischemic brain injury in a mouse model of transient middle cerebral artery occlusion (tMCAO). Methods Circulating human EPCs were characterized with immunofluorescent staining and flow cytometry. EPCs (1 × 106) were injected into nude mice after 1 hour of tMCAO. Histological analysis and behavioral tests were performed from day 0 to 28 days after tMCAO. Results EPCs were detected in ischemic brain regions 24 hours after tMCAO. EPC transplantation significantly reduced ischemic infarct volume at 3 days after tMCAO compared with control animals (p < 0.05). CXCR4 was expressed in the majority of EPCs, and stromal-derived factor-1 (SDF-1) induced EPC migration, which was blocked by pretreated EPCs with AMD3100 in vitro. SDF-1 was upregulated in ischemic brain. Compared with control animals, injecting AMD3100-pretreated EPCs resulted in a larger infarct volume 3 days after tMCAO, suggesting that SDF-1,mediated signaling was involved in EPC-mediated neuroprotection. In addition, EPC transplantation reduced mouse cortex atrophy 4 weeks after tMCAO and improved neurobehavioral outcomes (p < 0.05). EPC injection potently increased angiogenesis in the peri-infarction area (p < 0.05). Interpretation We conclude that systemic delivery of EPCs protects the brain against ischemic injury, promotes neurovascular repair, and improves long-term neurobehavioral outcomes. Our data suggest that SDF-1,mediated signaling plays a critical role in EPC-mediated neuroprotection. ANN NEUROL 2010;67:488,497 [source] | |||||||||||||