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Subcutaneous Implants (subcutaneous + implant)
Selected AbstractsHIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokinesGLIA, Issue 2 2006Nazira El-Hage Abstract Opiates exacerbate human immunodeficiency virus type 1 (HIV-1) Tat1-72 -induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in particular, is potentiated by opiate,HIV Tat interactions in vitro. Although MCP-1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, the role of MCP-1 in neuro-acquired immunodeficiency syndrome (neuroAIDS) progression in opiate abusers, or nonabusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was found to be significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat1-72 than in vehicle-, ,-opioid receptor (MOR) antagonist-, or inactive, mutant Tat,31-61 -treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP-1 antibodies, or medium from MCP-1,/, astrocytes. In the presence of morphine (time-release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post-injection. This was not seen after treatment with Tat alone, or with morphine plus inactive Tat,31-61 or naltrexone. Glia displayed increased MOR and MCP-1 immunoreactivity after morphine and/or Tat exposure. The findings indicate that MCP-1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial-derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate-driven amplification/positive feedback of MCP-1 production and inflammation. © 2005 Wiley-Liss, Inc. [source] Mitigating Photosensitivity of Erythropoietic Protoporphyria Patients by an Agonistic Analog of ,-Melanocyte Stimulating Hormone,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 6 2009Juergen H. Harms Erythropoietic protoporphyria (EPP) is a rare hereditary disorder characterized by dermal accumulation of the photosensitizer protoporphyrin IX. Following sunlight exposure, the resulting photosensitivity is manifested first as pain, later as erythema, edema and dermal lesions. Afamelanotide (Nle4 -d-Phe7 -,-MSH), a synthetic analog of ,-melanocyte stimulating hormone and agonist of the melanocortin-1-receptor, promotes melanin synthesis, increasing skin pigmentation. This study examines the efficacy of afamelanotide in preventing symptoms in patients with EPP. A sustained-release subcutaneous implant of 20 mg afamelanotide was administered twice, with a 60-day interval to five EPP patients. Therapeutic efficacy was assessed by a photoprovocation test using standardized white light irradiation, melanin density (MD) determination and daily recording of sunlight exposure and symptoms. From Day 30 to Day 120 tolerance to photoprovocation significantly increased compared with baseline (P = 0.007) and skin MD was significantly higher than that recorded at baseline (P = 0.004). Except for two low-grade pain episodes, patients recorded no phototoxic events past Day 4 of treatment. Tolerance to natural sunlight was up to 24 times longer than prior to therapy. The findings demonstrate beneficial effects of afamelanotide in patients with EPP. Due to the limited number of patients enrolled and the design being an open-label study, confirmation by a large-scale trial is required. [source] Augmentation of osseous phenotypes in vivo with a synthetic peptideJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2007Xinhua Lin Abstract The synthetic peptide B2A2-K-NS augmented the in vitro expression of osseous phenotypes when cells were stimulated with BMP-2, an osteoinductive growth factor. B2A2-K-NS significantly enhanced the effects of BMP-2-induced alkaline phosphatase activity and mineralization. In the absence of BMP-2, B2A2-K-NS did not have an effect on these endpoints. Based on these observations, in vivo studies were conducted to evaluate if B2A2-K-NS could augment osseous phenotypes in an osteoinductive environment in which BMP-2 should be present. In one study, human demineralized bone matrix (DBM) was used to generate an osteoinductive environment and the effects of B2A2-K-NS on ectopic mineralization of subcutaneous implants evaluated. In the second study, a noncritical sized defect in rabbit ulnas with inherent reparative capacity was used as the osteoinductive environment and was treated with or without B2A2-K-NS. In the DBM studies, B2A2-K-NS augmented mineralization as determined using a combination of radiographic analysis and von Kossa staining at 4 weeks postimplant. In the rabbit ulna model, B2A2-K-NS significantly increased the radiographic bone density in the defects compared to carrier-only or no-treatment controls after 6 weeks. Histological staining confirmed that B2A2-K-NS generated a pronounced bone repair response. The results are consistent with the hypothesis that B2A2-K-NS augments osseous phenotypes in an osteoinductive environment, and suggests that B2A2-K-NS may have clinical utility. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:531,539, 2007 [source] In-vitro and in-vivo characterization of a buprenorphine delivery systemJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2006Sofie R. Kleppner Buprenorphine is a mu-opioid receptor partial agonist with enhanced safety and comparable efficacy to methadone for treatment of opioid dependence. The sublingual formulation of buprenorphine, approved for treatment of opioid dependence, produces variable buprenorphine blood levels and requires frequent dosing that limits patient compliance. To achieve stable buprenorphine levels that may improve patient outcome, an implantable sustained buprenorphine delivery system was developed. Each implant consists of ethylene vinyl acetate copolymer and 90 mg buprenorphine HCl, and measures 26 mm in length and 2.4 mm in diameter. Steady-state release in-vitro was 0.5 mg/implant/day. In-vivo pharmacokinetics and safety were examined for up to 52 weeks in beagle dogs receiving 8, 16 or 24 subcutaneous implants. Plasma buprenorphine concentrations correlated with the number of implants administered. Peak buprenorphine concentrations were generally reached within 24 h after implantation. Steady-state plasma levels were attained between 3 and 8 weeks, and were maintained for study duration, with a calculated mean release rate of 0.14 ± 0.04 mg/implant/day. There were no test-article-related adverse effects. This delivery system can provide long-term stable systemic buprenorphine levels, and may increase patient compliance, thereby improving outcome for opioid-dependent patients. [source] Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanismsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2007R. GRANATA Summary. Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin-like growth factor binding protein (IGFBP)-3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP-3 plays a role in promoting angiogenesis. IGFBP-3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up-regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 and -9. IGFBP-3 even induced membrane-type 1 MMP (MT1-MMP), which regulates MMP-2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP-3-induced network formation and inhibited VEGF, MT1-MMP but not IGF-I up-regulation. IGF-I activated SphK, leading to sphingosine-1-phosphate (S1P) formation. The IGF-I effect on SphK activity was blocked by specific inhibitors of IGF-IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF-I signaling prevented the IGFBP-3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF-I up-regulation. Finally, IGFBP-3 dose-dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo. Thus, IGFBP-3 positively regulates angiogenesis through involvement of IGF-IR signaling and subsequent SphK/S1P activation. [source] Eicosapentaenoic acid and docosahexaenoic acid effects on tumour mitochondrial metabolism, acyl CoA metabolism and cell proliferationCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2001Alison Colquhoun Abstract In order to investigate the effects of high-fat diets rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), Wistar rats bearing subcutaneous implants of the Walker 256 tumour were fed pelleted chow containing low DHA/EPA or high DHA/EPA. The presence of n -3 polyunsaturated fatty acids (PUFAs) led to a marked suppression (35,46%) of tumour growth over a 12 day period. Both the whole tumour homogenate and the Percoll-purified mitochondrial fraction presented significant changes in fatty acid composition. The levels of EPA increased in both n -3 dietary groups while the levels of DHA increased only in the high DHA/EPA group, in comparison with the control chow-fed group. The presence of n -3 PUFAs led to an increase in mitochondrial acyl CoA synthetase activity, but neither the cytoplasmic acyl CoA content nor the n -3 fatty acid composition of the cytoplasmic acyl CoAs was altered by the diet. The content of thiobarbituric acid-reactive substances (TBARS) was increased in the low DHA/EPA group but was unchanged in the high DHA/EPA group. In vitro studies with the Walker 256 cell line showed a 46% decrease in cell growth in the presence of either EPA or DHA which was accompanied by a large decrease in the measured mitochondrial membrane potential. The TBARS content was increased only in the EPA-exposed cells. Cell cycle analysis identified a decrease in G0,G1 phase cells and an increase in G2,M phase cells and apoptotic cells, for both EPA and DHA-exposed cells. The data show that the presence of n -3 PUFAs in the diet is able to significantly after the growth rate of the Walker 256 tumour. The involvement of changes in mitochondrial membrane composition and membrane potential have been indicated for both EPA and DHA, while changes in lipid peroxidation have been identified in the presence of EPA but not of DHA. Copyright © 2001 John Wiley & Sons, Ltd. [source] | |||||||||||||