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Retinoids
Kinds of Retinoids Terms modified by Retinoids Selected AbstractsRetinoid- and carotenoid-enriched diets influence the ontogenesis of the immune system in miceIMMUNOLOGY, Issue 2 2003Ada L. Garcia Summary Vitamin A (VA) has been identified as an important factor for the development of the immune system, especially during ontogenesis. It has been shown that antibody secretion and proliferation of lymphocyte populations depend on retinoids. In the present study we investigated the influence of a base VA diet and diets enriched with VA, ,-carotene and lycopene, on the ontogenesis of the immune system in mice. We examined the absolute and relative concentrations of splenic B lymphocytes (CD45R/B220), T lymphocytes (CD3+) and their subpopulations (CD4+ and CD8+), and measured serum immunoglobulin G (IgG) concentrations in the offspring of supplemented dams at different ages (1, 3, 5, 7, 14, 21 and 65 days). The experimental diets resulted in higher numbers of T and B lymphocytes after VA and carotenoid enrichment, when compared, at various time-points, with the base diet. Higher values of total serum IgG were found in the ,-carotene-enriched diet group on day 7. On days 7 and 14, the enriched diets induced significant alterations in the percentages and total numbers of splenic lymphocytes in comparison to the base diet. Our results confirm that supplementation with VA and carotenoids affect the immune-cell function during ontogenesis and suggest a possible role of these nutritional factors on the development of the immune system. [source] Is the modulation of retinoid and retinoid-associated signaling a future therapeutic strategy in neurological trauma and neurodegeneration?JOURNAL OF NEUROCHEMISTRY, Issue 3 2008Andrea Malaspina Abstract The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels. Finally, we summarize the potential therapeutic avenues based on the modulation of retinoid targets undergoing reactivation under conditions of acute injury and chronic degeneration in the central nervous system, and discuss some of the unresolved issues linked to this treatment strategy. [source] Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivoARTHRITIS & RHEUMATISM, Issue 10 2009Naho Ohyanagi Objective Polymyositis and dermatomyositis are chronic inflammatory muscle diseases. Retinoids are compounds that bind to the retinoic acid binding site of retinoic acid receptors and have biologic activities similar to those of vitamin A. Recent studies indicate that retinoids promote Th2 differentiation and suppress Th1 and Th17 differentiation in vitro. The present study was undertaken to examine the effects of a synthetic retinoid, Am80, on experimental autoimmune myositis as well as on Th phenotype development and antibody production. Methods Experimental autoimmune myositis was induced in SJL/J mice by immunization with rabbit myosin. Am80 was administered orally once daily. Its effects were evaluated by measurement of the numbers of infiltrating inflammatory cells, production of inflammatory cytokines in muscle, production of Th-specific cytokines by myosin-stimulated splenic T cells, and production of antimyosin antibodies in serum. Results In mice with experimental autoimmune myositis, orally administered Am80 significantly reduced the number of infiltrating inflammatory cells and the expression of tumor necrosis factor , and interleukin-1, (IL-1,) in muscle. Moreover, Am80 increased production of interferon-,, IL-4, and IL-10, but not IL-17, by myosin-stimulated splenic T cells of mice with experimental autoimmune myositis, suggesting that it could enhance differentiation into Th1 and Th2, but not Th17, in vivo. Am80 also decreased serum levels of IgG2a and IgG2b antimyosin antibodies, but did not affect levels of IgG1 antimyosin antibodies. In addition, it suppressed chemokine expression and activator protein 1 activity in myoblasts in vitro. Conclusion The synthetic retinoid Am80 has an inhibitory effect on experimental autoimmune myositis. It might regulate the development of Th phenotype and antibody production in vivo, in addition to its effects on cytokine and chemokine production. [source] Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid ReceptorsCHEMBIOCHEM, Issue 7 2009José García Abstract RAR and RXR agonists: A collection of pyrazine-based RAR/RXR ligands were prepared by a series of palladium catalyzed cross-coupling reactions and characterized. Structure,activity relationships were elucidated. Retinoic acid receptor (RAR) ,/,-subtype-selective and retinoid X receptor (RXR) inverse agonist activities are described for pyrazine acrylic acid arotinoid, 14,d. Heterocyclic arotinoids derived from central-region dihalogenated pyrazine scaffolds have been synthesized by consecutive halogen and/or position-selective palladium-catalyzed cross-coupling reactions. Pyrazines were further functionalized as alkyl ethers or methylamines prior to the last Pd-catalyzed reactions. Transient transactivation studies with the retinoic acid receptor (RAR) ,, ,, and , subtypes and with retinoid X receptor (RXR) , revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RAR,,,-selective inverse agonists with pyrazine acrylic acid structures, in particular 14,c, which is RAR,-selective, and 14,d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors. [source] Oestradiol and SERM treatments influence oestrogen receptor coregulator gene expression in human skeletal muscle cellsACTA PHYSIOLOGICA, Issue 3 2009C. M. Dieli-Conwright Abstract Aim:, Oestrogen receptors (ER) are present in human skeletal muscle (hSkM) cells; however, the function of the receptor is currently unknown. We investigated the influence of oestradiol and selective ER modulators [tamoxifen (TAM), raloxifene (RAL)] on ER coregulator mRNA expression in hSkM. Methods:, Human skeletal muscle cells were treated with 10 nm oestradiol, 5 ,m TAM and 10 ,m RAL over a 24-h period. Following the treatment period, mRNA expression was quantified using real-time PCR to detect changes in ER-,, ER-,, steroid receptor coactivator (SRC), silencing mediator for retinoid and thyroid hormone receptors (SMRT), MyoD, GLUT4 and c-fos. Results:, ER-, mRNA expression increased with all three drug treatments (P < 0.05) while there was no change in mRNA expression of ER-, in hSkM cells. mRNA expression of SRC increased and SMRT decreased with oestradiol, TAM and RAL in hSkM cells (P < 0.05). Importantly, mRNA expression of MyoD increased with oestradiol and decreased with TAM and RAL in hSkM cells (P < 0.05). mRNA expression of GLUT4 increased with oestradiol and RAL and decreased with TAM in hSkM cells (P < 0.05). Conclusions:, These findings are novel in that they provide the first evidence that oestradiol and selective ER modulators influence ER-, function in hSkM cells. This demonstrates the importance of the ER and alterations in its coregulators, to potentially prevent sarcopenia and promote muscle growth in postmenopausal women using these forms of hormone replacement therapy. [source] Treatment of cutaneous T-cell lymphoma with retinoidsDERMATOLOGIC THERAPY, Issue 5 2006Chunlei Zhang ABSTRACT:, Retinoids are biologic regulators of differentiation, proliferation, apoptosis, and immune response. Retinoids (all- trans retinoic acid, 13- cis -retinoic acid, and the synthetic analogs isotretinoin, etretinate, and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphomas (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid X receptor retinoid to be approved by the Food and Drug Administration for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Use of retinoids in future long-term clinical trials and their eventual application in CTCL regiments will require strategies to decrease the side effects of existing retinoids, identify novel receptor subtype-selective retinoids with better therapeutic index, and explore biologically based synergistic combination therapies with other active agents. [source] Pre-activation of retinoid signaling facilitates neuronal differentiation of mesenchymal stem cellsDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2010Yang Bi Mesenchymal stem cells (MSCs) can differentiate into neurons in an appropriate cellular environment. Retinoid signaling pathway is required in neural development. However, the effect and mechanism through retinoid signaling regulates neuronal differentiation of MSCs are still poorly understood. Here, we report that all-trans-retinoic acid (ATRA) pre-induction improved neuronal differentiation of rat MSCs. We found that, when MSCs were exposed to different concentrations of ATRA (0.01,100 ,mol/L) for 24 h and then cultured with modified neuronal induction medium (MNM), 1 ,mol/L ATRA pre-induction significantly improved neuronal differentiation efficiency and neural-cell survival. Compared with MNM alone induced neural-like cells, ATRA/MNM induced cells expressed higher levels of Nestin, neuron specific enolase (NSE), microtubule-associated protein-2 (MAP-2), but lower levels of CD68, glial fibrillary acidic protein (GFAP), and glial cell line-derived neurotrophic factor(GDNF), also exhibited higher resting membrane potential and intracellular calcium concentration, supporting that ATRA pre-induction promotes maturation and function of derived neurons but not neuroglia cells from MSCs. Endogenous retinoid X receptors (RXR) RXR, and RXR, (and to a lesser extent, RXR,) were weakly expressed in MSCs. But the expression of RAR, and RAR, was readily detectable, whereas RAR, was undetectable. However, at 24 h after ATRA treatment, the expression of RAR,, not RAR, or RAR,, increased significantly. We further found the subnuclear redistribution of RAR, in differentiated neurons, suggesting that RAR, may function as a major mediator of retinoid signaling during neuronal differentiation from MSCs. ATRA treatment upregulated the expression of Vimentin and Stra13, while it downregulated the expression of Brachyury in MSCs. Thus, our results demonstrate that pre-activation of retinoid signaling by ATRA facilitates neuronal differentiation of MSCs. [source] Role for retinoid signaling in left,right asymmetric digestive organ morphogenesisDEVELOPMENTAL DYNAMICS, Issue 8 2006Kristen Lipscomb Abstract The looping events that establish left,right asymmetries in the vertebrate gut tube are poorly understood. Retinoic acid signaling is known to impact left,right development in multiple embryonic contexts, although its role in asymmetric digestive organ morphogenesis is unknown. Here, we show that the genes for retinaldehyde dehydrogenase (RALDH2) and a retinoic acid hydroxylase (CYP26A1) are expressed in complementary patterns in the Xenopus gut during looping. A late-stage chemical genetic assessment reveals that agonists and antagonists of retinoid signaling generate abnormal gut looping topologies, digestive organ heterotaxias, and intestinal malrotations. Accessory organ deformities commonly associated with intestinal malrotation in humans, such as annular pancreas, pancreas divisum, and extrahepatic biliary tree malformations, are also induced by distinct retinoid receptor agonists. Thus, late-stage retinoic acid signaling is likely to play a critical role in asymmetric gut tube morphogenesis and may underlie the etiology of several clinically relevant defects in the digestive system. Developmental Dynamics 235:2266,2275, 2006. © 2006 Wiley-Liss, Inc. [source] Effect of tributyltin on testicular development in Sebastiscus marmoratus and the mechanism involved,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2009Jiliang Zhang Abstract Organotin compounds, such as tributyltin (TBT), that have been used as antifouling biocides can induce masculinization in female mollusks. However, few studies addressing the effects of TBT on fishes have been reported. The present study was conducted to investigate the effects of TBT at environmentally relevant concentrations (1,10, and 100 ng/L) on testicular development in Sebastiscus marmoratus and to gain insight into its mechanism of action. After exposure for 48 d, the gonadosomatic index had decreased in a dose-dependent manner. Although the testosterone levels in the testes were elevated and the 17,-estradiol levels were decreased, spermatogenesis was suppressed. Moreover, ,-glutamyl transpeptidase activity (which is used as a Sertoli cell marker) was decreased in a dose-dependent manner after TBT exposure, and serious interstitial fibrosis was observed in the interlobular septa of the testes in the 100 ng/L TBT test group. Increases in the retinoid × receptors and peroxisome proliferator activated receptor , expression and the progressive enlargement of lipid droplets in the testes were observed after TBT exposure. Estrogen receptor , levels in the testes of the fish exposed to TBT decreased in a dose-dependent manner. The reduction of estrogen receptor , mRNA resulted from the decrease of 17,-estradiol levels, and the progressive enlargement of lipid droplets may have contributed to the dysfunction of the Sertoli cells, which then disrupted spermatogenesis. [source] Evaluation of ecotoxicity and fate of methylated butyltins in sediments and seawater from Tokyo Bay, JapanENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2007Ryo Kurihara Abstract We analyzed the fate of organotins in seawater and sediments from Tokyo Bay, Japan, by gas chromatography/inductively coupled plasma mass spectrometry. We also measured the toxicity of methylated butyltins by in vitro bioassays, the retinoid × receptor (RXR) activation method, and the marine luminescent bacterium Vibrio fischeri. Concentrations of tributyltin (TBT) and tributylmonomethyltin (TBMMT) in seawater were 0.0636 to 0.419 and 0.0050 to 0.108 ng Sn/L and in sediment were 7.51 to 17.8 and 3.67 to 6.87 ng Sn/wet weight g, respectively. Methylated butyltins did not activate RXR and were not toxic to bacteria. Tributylmonomethyltin in seawater would elute from sediment since TBMMT-to-TBT ratios showed a positive correlation (r2 = 0.858) between sediment and deep seawater. Both methylation and debutylation of TBT seem to be major routes of decomposition of TBT in sediment. Methylation of TBT would not only cause subsequent volatilization but also decrease the toxicity of TBT species in the marine environment. [source] Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoidsHEPATOLOGY, Issue 1 2004Karine Hellemans Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9- cisRA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All- trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli. (HEPATOLOGY 2004;39:97,108.) [source] Isotretinoin and the controversy of psychiatric adverse effectsINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 7 2006Jamison E. Strahan MD Isotretinoin is a synthetic oral retinoid that has great efficacy against severe, recalcitrant, nodulocystic acne. Since its introduction to the market, it has been associated with a variety of adverse psychiatric effects, including depression, psychosis, mood swings, violent behavior, suicide, and suicide attempts. A MEDLINE review was performed to compile all case reports, case series, adverse drug event reportings, and prospective and retrospective studies relating psychiatric adverse events to isotretinoin. In addition, literature linking a biological mechanism for psychiatric adverse events to retinoid signaling pathways was also reviewed. Although a variety of anecdotal and epidemiologic studies are available, the overall lack of concrete scientific data limits any conclusion that can be drawn about a causal relationship between istotretinoin and psychiatric adverse events. Several lines of evidence link retinoid signaling to theorized psychiatric pathogenesis, but are limited in their applicability to adult neurophysiology. [source] Is the modulation of retinoid and retinoid-associated signaling a future therapeutic strategy in neurological trauma and neurodegeneration?JOURNAL OF NEUROCHEMISTRY, Issue 3 2008Andrea Malaspina Abstract The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels. Finally, we summarize the potential therapeutic avenues based on the modulation of retinoid targets undergoing reactivation under conditions of acute injury and chronic degeneration in the central nervous system, and discuss some of the unresolved issues linked to this treatment strategy. [source] Prospective, open-label, comparative study of clindamycin 1%/benzoyl peroxide 5% gel with adapalene 0.1% gel in Asian acne patients: efficacy and tolerabilityJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 3 2009H-C Ko Abstract Background, Used as individual agents, topical antibiotics and benzoyl peroxide are known to be effective in treatment of acne. Clindamycin phosphate 1% with benzoyl peroxide 5% (CDP/BPO) is a new combination gel, made by rationale, in that combination drug is more effective than either ingredients used alone. Adapalene 0.1% (ADA) is the third-generation retinoid, shown to be as effective as other topical retinoid with well tolerability. Objectives, To compare the efficacy and tolerability in combination of CDP/BPO in comparison with ADA in Asian patients with mild to moderate acne vulgaris. Methods, Total of 69 patients, including 31 patients for CDP/BPO group and 38 for ADA group, with mild to moderate acne vulgaris were enrolled for a 12-week prospective, randomized, open-label comparative study of topical agents. Efficacy was assessed by lesion counts, acne grading system, and global improvement. Adverse events were also evaluated in scale of 0 (none) to 3 (severe). Results, Both CDP/BPO and ADA were effective in reducing lesion counts and acne severity scale and showed significant global improvement. However, CDP/BPO offered greater efficacy against inflammatory lesions than ADA. Both drugs were well tolerated with minimal adverse drug reactions. Conclusion, Combination formulation of CDP/BPO and ADA were shown to be both effective in decreasing total, inflammatory, and non-inflammatory lesion counts along with well tolerability in Asian patients with mild to moderate acne vulgaris. Conflicts of interest None declared [source] Transcriptional regulation of connexin 43 expression by retinoids and carotenoids: Similarities and differencesMOLECULAR CARCINOGENESIS, Issue 2 2005Alex L. Vine Abstract Gap junctions, connexons, are formed by assembly of trans-membrane connexin proteins and have multiple functions including the coordination of cell responses. Most human tumors are deficient in gap junctional communication (GJC) and restoration of GJC by forced expression of connexins reduces indices of neoplasia. Expression of connexin 43 (Cx43), the most widely-expressed connexin family member, is upregulated by cancer-preventive retinoids and carotenoids in normal and preneoplastic cells; an action considered of mechanistic significance. However, the molecular mechanism for upregulated expression is poorly understood. The retinoic acid receptor antagonist Ro 41-5253 was capable of suppressing retinoid-induction Cx43 luciferase reporter construct in F9 cells, but did not suppress reporter activity induced by the non-pro-vitamin A carotenoids astaxanthin or lycopene, indicating that retinoids have separate mechanisms of gene activation than non-pro-vitamin A carotenoids. Neither class of compound required protein synthesis for induction of Cx43 mRNA, nor was the 5.0 h half-life of Cx43 mRNA altered, indicating direct transcriptional activation. The responsive region was found within ,158 bp and +209 bp of the transcription start site; this contains a Sp1/Sp3 GC-box to which Sp1 and Sp3 were bound, as revealed by electrophoretic mobility shift assays (EMSA), but no retinoic acid response element (RARE). Site directed mutagenesis of this GC-box resulted in increased basal levels of transcription and loss of responsiveness to a synthetic retinoid. In this construct astaxanthin and lycopene produced marginally, but not significantly higher, reporter activity than the control. © 2005 Wiley-Liss, Inc. [source] Effect of Visible Light on Normal and P23H-3 Transgenic Rat Retinas: Characterization of a Novel Retinoic Acid Derivative Present in the P23H-3 RetinaPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2006Todd Duncan ABSTRACT Transgenic rats with the P23H mutation in rhodopsin exhibit increased susceptibility to light damage, compared with normal animals. It is known that light-induced retinal damage requires repetitive bleaching of rhodopsin and that photoreceptor cell loss is by apoptosis; however, the underlying molecular mechanism(s) leading to photoreceptor cell death are still unknown. Photoproducts, such as all- trans retinal or other retinoid metabolites, released by the extensive bleaching of rhodopsin could lead to activation of degenerative processes, especially in animals genetically predisposed to retinal degenerations. Using wild-type and transgenic rats carrying the P23H opsin mutation, we evaluated the effects of acute intense visible light on retinoid content, type and distribution in ocular tissues. Rats were exposed to green light (480,590 nm) for 0, 5, 10, 30 and 120 min. Following light treatment, rats were sacrificed and neural retinas were dissected free of the retinal pigment epithelium. Retinoids were extracted from retinal tissues and then subjected to HPLC and mass spectral analysis. We found that the light exposure affected relative levels of retinoids in the neural retina and retinal pigment epithelium of wild-type and P23H rat eyes similarly. In the P23H rat retina but not the wild-type rat retina, we found a retinoic acid-like compound with an absorbance maximum of 357 nm and a mass of 304 daltons. Production of this retinoic acid-like compound in transgenic rats is influenced by the age of the animals and the duration of light exposure. It is possible that this unique retinoid may be involved in the process of light-induced retinal degeneration. [source] Latest news and product developmentsPRESCRIBER, Issue 8 2008Article first published online: 12 MAY 200 Glargine preferred to lispro as type 2 add-on Basal insulin glargine (Lantus) and insulin lispro (Humalog) at mealtimes improved glycaemic control equally well in patients with type 2 diabetes poorly controlled by oral agents, but patient satisfaction was greater with basal insulin (Lancet 2008;371:1073-84). The 44-week APOLLO trial, funded by Sanofi Aventis, was a nonblinded randomised comparison of basal and prandial insulin regimens added to oral treatment in 418 patients. It found similar reductions in HbA1C (,1.7 vs ,1.9 per cent respectively). Fasting and nocturnal glucose levels were lower with insulin glargine and postprandial levels were lower with insulin lispro. The basal regimen was associated with fewer hypoglycaemic events (5.2 vs 24 per patient per year), less weight gain (3.01 vs 3.54kg) and greater improvement in patient satisfaction scores. Treating hypertension cuts mortality in over-80s Treating hypertension in the over-80s reduces all-cause mortality by 21 per cent, the HYVET study has shown (N Engl J Med online: 31 March 2008; doi: 10.1056/NEJMoa 0801369). Compared with placebo, treatment with indapamide alone or with perindopril for an average of 1.8 years also reduced the incidence of fatal stroke by 39 per cent, cardiovascular death by 23 per cent and heart failure by 64 per cent. The incidence of stroke was reduced by 30 per cent but this was of borderline statistical significance. Fewer serious adverse events were reported with treatment than with placebo. New work for NICE The DoH has announced the 18th work programme for NICE. Seven public health interventions include preventing skin cancer, smoking by children and excess weight gain during pregnancy. Public health guidance will include the provision of contraceptive services for socially disadvantaged young people. Two new clinical guidelines are sedation in young people and management of fractured neck of femur. New technology appraisals may include eight therapies for cancer, two new monoclonal antibodies for psoriasis and rheumatoid arthritis, an oral retinoid for severe chronic hand eczema and methylnaltrexone for opioid-induced bowel dysfunction. Combinations no better against CV disease Taking ezetimibe and simvastatin (Inegy) does not appear to slow the progression of atherosclerosis more than high-dose simvastatin alone, say researchers from The Netherlands (N Engl J Med 2008;358: 1431-43). In patients with hypercholesterolaemia, there was no difference in regression or progression of atherosclerosis after two years' treatment with simvastatin 80mg per day alone or combined with ezetimibe 10mg per day. Adverse event rates were similar. In patients with vascular disease or high-risk diabetes, there was no difference between the ACE inhibitor ramipril 10mg per day or the ARB telmisartan (Micardis) 80mg per day as monotherapy, or their combination, in the risk of a composite outcome of cardiovascular death, MI, stroke and admission for heart failure (N Engl J Med 2008;358:1547-59). Combined treatment was associated with higher risks of hypotensive symptoms, syncope and renal dysfunction. Twice-daily celecoxib increases CV risk Taking celecoxib (Celebrex) twice daily carries a higher risk of cardiovascular events than the same total dose taken once daily, a metaanalysis suggests (Circulation 2008; doi: 10.1161/ CIRCULATIONAHA.108. 764530). The analysis of six placebo-controlled trials involving a total of 7950 patients taking celecoxib for indications other than rheumatoid arthritis found that the combined risk of cardiovascular death, myocardial infarction, stroke, heart failure or thromboembolic event increased with dose over the range 400-800mg per day. The risk was significantly greater with 200mg twice daily (HR 1.8) than 400mg once daily (HR 1.1). Patients at greatest baseline risk were at disproportionately increased risk from celecoxib. Long-term etanercept effective in AS An open-label study suggests that etanercept (Enbrel) remains effective in the treatment of ankylosing spondylitis in the long term (Ann Rheum Dis 2008;67:346-52). Of 257 patients who completed six months' treatment with etanercept and who entered the nonblinded extension study, 126 completed a total of 168-192 weeks' treatment. The commonest adverse events were injection-site reactions (22 per cent), headache (20 per cent) and diarrhoea (17.5 per cent). The annual rate of serious infections was 0.02 per person. Response and partial remission rates after 192 weeks were similar to those reported after 96 weeks. Metformin reduces risk Metformin reduces the risk of developing diabetes in individuals at increased risk, a meta-analysis suggests (Am J Med 2008;121:149-57.e2). The study included 31 mostly small, randomised, controlled trials involving a total of 4570 participants and lasting at least eight weeks (8267 patient-years of treatment). Metformin was associated with reductions in body mass (,5.3 per cent), fasting glucose (,4.5 per cent) and insulin resistance (,22.6 per cent); lipid profiles also improved. The odds of developing diabetes were reduced by 40 per cent,an absolute risk reduction of 6 per cent over 1.8 years. MHRA clarifies cough and colds advice Press reports mistakenly suggested that the MHRA had banned some cough and cold remedies when it issued new guidance on treating young children, the MHRA says. The Agency's advice followed a review of over-thecounter cough and cold medicines for children by the Commission on Human Medicines. Children under two are at increased risk of adverse reactions and should no longer be treated with products containing antihistamine (chlorphenamine, brompheniramine, diphenhydramine), antitussives (dextromethorphan, pholcodine), expectorants (guaifenesin, ipecacuanha) and decongestants (phenylephrine, pseudoephedrine, ephedrine, oxymetazoline and xylometazoline). The MHRA said these products, which are classified as general sale medicines, should be removed from open shelves until available in new packaging that complies with the advice. They may still be supplied by a pharmacist for the treatment of older children. Coughs and colds should be treated with paracetamol or ibuprofen for fever, a simple glycerol, honey or lemon syrup for cough, and vapour rubs and inhalant decongestants for stuffy nose. Saline drops can be used to thin and clear nasal secretions in young babies. Parents are being urged not to use more than one product at a time to avoid inadvertently administering the same constituent drug twice. Perindopril brand switch Servier Laboratories is replacing its current formulations of perindopril (Coversyl, Coversyl Plus) with a new product that is not bioequivalent. The current Coversyl brand contains perindopril erbumine (also known as tert -butylamine). The new formulation contains perindopril arginine; it will be distinguished by new brand names (Coversyl Arginine, Coversyl Arginine Plus) and new packaging. Coversyl 2, 4 and 8mg tablets are equivalent to Coversyl Arginine 2.5, 5 and 10mg. Servier says the change is part of the simplification and harmonisation of global manufacturing; the arginine salt is already used in other countries and offers greater stability and a longer shelf-life. Both Coversyl and Coversyl Arginine will be in the supply chain for the next few weeks. Generic perindopril will continue to be the erbumine salt and prescriptions for generic perindopril are not affected. New from NICE Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. Clinical Guidance No. 63, March 2008 This clinical guideline focuses on additional aspects of care for women with gestational diabetes (88 per cent of cases) or pre-existing diabetes (of which about 40 per cent is type 2 diabetes) and their babies. To date, insulin aspart (NovoRapid) is the only drug in the guideline specifically licensed for use in pregnancy and NICE advises obtaining informed consent to implement its recommendations for using other insulins and oral hypoglycaemic agents. As with other guidelines, NICE begins by stressing the importance of patient-centred care and involving women in decisions about their treatment. The guideline is divided into six sections, dealing with consecutive periods of pregnancy. Preconceptual planning should include empowering women to help them reduce risks, optimising glycaemic control (after retinal assessment) and increasing monitoring intensity, and providing information about the effects of pregnancy on diabetes. Metformin may be recommended as an adjunct or alternative to insulin, but other oral hypoglycaemic agents should be replaced with insulin, although glibenclamide is an option during pregnancy. Isophane insulin is the preferred long-acting insulin; lispro (Humalog) and aspart are considered safe to use. ACE inhibitors and angiotensin-II receptor blockers should be replaced with other antihypertensive agents and statins should be discontinued. Recommendations for screening and treatment of gestational diabetes build on previous guidance (CG62). Drug treatment will be needed by 10-20 per cent , this includes insulin (soluble, aspart or lispro) and/or metformin or glibenclamide, tailored to individual need. Antenatal care includes optimising glycaemic control. Insulin lispro or aspart should be considered in preference to soluble insulin. If glycaemic control cannot be achieved with insulin injections, an insulin pump may be indicated. The guideline includes a timetable for appointments and the care that should offered after each interval. Recommendations for intrapartum care, which supplement those in CG55, include frequent monitoring of blood glucose. Neonatal care includes recommendations for monitoring and screening the infant and the management of hypoglycaemia. Postnatal care (supplementing CG37) involves adjusting maternal treatment to avoid hypoglycaemia and recommendations for returning to community care. Metformin and glibenclamide are the only oral agents suitable for breastfeeding women. Women with gestational diabetes need advice about glycaemic control and planning for future pregnancies. Lifestyle advice and measurement of annual fasting plasma glucose should be offered. Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over. Technology Appraisal No. 138, March 2008 The latest technology appraisal of asthma treatments covers inhaled steroids for adults and children over 12 with chronic asthma. It makes only two recommendations. First, the cheapest appropriate option is recommended. Second, when a steroid and a long-acting beta2-agonist are indicated, the decision to prescribe a combined inhaler or separate devices should take into account therapeutic need and likely adherence. Combined inhalers are currently less expensive than separate devices, though they may not remain so. When a combined inhaler is chosen it should be the cheapest. NICE concludes that, at equivalent doses, there is little difference in the effectiveness or adverse event profile of the available steroids or the fixed-dose combinations. According to specialist advice, choosing the best device for an individual remains the overriding concern. Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome. Technology Appraisal No. 139, March 2008 NICE recommends continuous positive airway pressure (CPAP) for adults with moderate or severe obstructive sleep apnoea, and for those with a milder disorder if quality of life and functioning are impaired and alternative strategies such as lifestyle change have failed. Diagnosis and treatment is the responsibility of a specialist team. A CPAP device costs £250-£550 and lasts for seven years. Copyright © 2008 Wiley Interface Ltd [source] Assignment of the porcine silencing mediator for retinoid and thyroid hormone receptors (NCOR2) to SSC14q21 by radiation hybrid mappingANIMAL GENETICS, Issue 3 2005Y. Song No abstract is available for this article. [source] Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivoARTHRITIS & RHEUMATISM, Issue 10 2009Naho Ohyanagi Objective Polymyositis and dermatomyositis are chronic inflammatory muscle diseases. Retinoids are compounds that bind to the retinoic acid binding site of retinoic acid receptors and have biologic activities similar to those of vitamin A. Recent studies indicate that retinoids promote Th2 differentiation and suppress Th1 and Th17 differentiation in vitro. The present study was undertaken to examine the effects of a synthetic retinoid, Am80, on experimental autoimmune myositis as well as on Th phenotype development and antibody production. Methods Experimental autoimmune myositis was induced in SJL/J mice by immunization with rabbit myosin. Am80 was administered orally once daily. Its effects were evaluated by measurement of the numbers of infiltrating inflammatory cells, production of inflammatory cytokines in muscle, production of Th-specific cytokines by myosin-stimulated splenic T cells, and production of antimyosin antibodies in serum. Results In mice with experimental autoimmune myositis, orally administered Am80 significantly reduced the number of infiltrating inflammatory cells and the expression of tumor necrosis factor , and interleukin-1, (IL-1,) in muscle. Moreover, Am80 increased production of interferon-,, IL-4, and IL-10, but not IL-17, by myosin-stimulated splenic T cells of mice with experimental autoimmune myositis, suggesting that it could enhance differentiation into Th1 and Th2, but not Th17, in vivo. Am80 also decreased serum levels of IgG2a and IgG2b antimyosin antibodies, but did not affect levels of IgG1 antimyosin antibodies. In addition, it suppressed chemokine expression and activator protein 1 activity in myoblasts in vitro. Conclusion The synthetic retinoid Am80 has an inhibitory effect on experimental autoimmune myositis. It might regulate the development of Th phenotype and antibody production in vivo, in addition to its effects on cytokine and chemokine production. [source] Hindbrain patterning revisited: timing and effects of retinoic acid signallingBIOESSAYS, Issue 11 2001Gerrit Begemann Retinoids play a critical role in patterning, segmentation, and neurogenesis of the posterior hindbrain and it has been proposed that they act as a posteriorising signal during hindbrain development. Until now, direct evidence that endogenous retinoid signalling acts through a gradient to specify cell fates along the anteroposterior axis has been missing. Two recent studies tested the requirement for retinoid signalling in the developing hindbrain through systematic application of a pan-retinoic acid receptor antagonist.(1,2) They demonstrate a stage-dependent requirement for increasing retinoid signalling activity along the hindbrain that proceeds from anterior to posterior. Together these findings challenge the concept of a stable gradient of retinoic acid across the hindbrain and warrant a re-interpretation of the phenotypes obtained by genetic and nutritional disruption of retinoid signalling in the amniote embryo. BioEssays 23:981,986, 2001. © 2001 John Wiley & Sons, Inc. [source] A multiparameter flow cytometric analysis of the effect of bexarotene on the epidermis of the psoriatic lesionBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2003M.E.J. Franssen Summary Background A new retinoid, bexarotene (Targretin®), was recently investigated in a large multicentre trial for its efficacy and safety in psoriasis. Bexarotene is a novel retinoid X receptor (RXR)-selective ligand. Objectives The aim was to study the effect of bexarotene in psoriasis by analysing markers for epidermal differentiation, proliferation and inflammation in epidermal single cell suspensions from lesions of patients with psoriasis treated with various doses of bexarotene. Methods Thirty-four patients with moderate to severe plaque psoriasis participated in this study and were assigned in sequence to four different dose regimens: 0·5, 1, 2 and 3 mg kg,1 once daily. Before and after 12 weeks of bexarotene treatment, punch biopsies were taken from lesional skin from which epidermal single cell suspensions were prepared using an optimized thermolysin protocol. A sum of scores was determined for each biopsy site, based on a four-point scale for erythema, induration and desquamation. An improved multiparameter flow cytometric assay was used that enabled simultaneous assessment of epidermal proliferation, various aspects of differentiation and epidermal inflammation. The following variables were measured simultaneously: relative DNA content, relative cell size, keratin (K) 10, K6 and vimentin expression. Results The psoriasis area and severity index (PASI) and sum of scores for the individual psoriatic lesion each showed a statistically significant decrease of 28% after 12 weeks of bexarotene treatment (P < 0·001). However, no significant dose,response effect was found. The total percentage of K10+ cells showed a significant increase of 43% (P < 0·01). The total population of K6 expressing cells did not show significant changes. Regarding the subpopulations of K6 single, K10 single and K6 and 10 co-expressing cells, a significant increase of 77% was seen in the K10+ K6, cells (P < 0·05), a significant decrease of 33% in K10, K6+ cells (P < 0·01), and no significant changes in the remaining population of K10+ K6+ cells. After 12 weeks of treatment with bexarotene no significant changes in epidermal proliferation and inflammation were shown. Conclusions The present study indicates a direct effect of RXR activation by bexarotene on the transition of proliferation-associated keratinization into normal keratinization. Although no direct effect of bexarotene on DNA content in the total K10, cells was shown, further studies on subpopulations within the germinative layer such as stem cells and transit amplifying cells might be worthwhile. [source] Ligands of the peroxisome proliferator-activated receptor- , and heart failureBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2004C Thiemermann Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR subfamily comprises of three members, PPAR- ,, PPAR- , and PPAR- ,. There is good evidence that ligands of PPAR- ,, including certain thiazolinediones, reduce myocardial tissue injury and infarct size. The use of PPAR- , agonists in the treatment of heart failure is, however, controversial. British Journal of Pharmacology (2004) 141, 1,3. doi:10.1038/sj.bjp.0705586 [source] Strategy and mechanism for the prevention of hepatocellular carcinoma: Phosphorylated retinoid X receptor , is a critical target for hepatocellular carcinoma chemopreventionCANCER SCIENCE, Issue 3 2009Masahito Shimizu Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is ,clonal deletion' therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXR, due to phosphorylation by the Ras,mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXR, proteins. In conclusion, the inhibition of RXR, phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXR,, may thus play a critical role in preventing the development of multicentric HCC. (Cancer Sci 2009; 100: 369,374) [source] Involvement of thioredoxin-binding protein 2 in the antitumor activity of CD437CANCER SCIENCE, Issue 12 2008Saori Matsuoka The present authors previously reported that a synthetic retinoid, CD437, induces endoplasmic reticulum stress-mediated apoptosis in ovarian adenocarcinoma cells in spite of no response to natural retinoids. However, the precise mechanism of its proapoptotic action has not been fully determined. The present study herein demonstrates that apoptosis induction of ovarian adenocarcinoma SKOV3 cells by CD437 involves the upregulation of thioredoxin-binding protein 2 (TBP2) by a mechanism that is dependent on the intracellular calcium concentration. TBP2 is known to bind to and suppress thioredoxin (TRX) activity whereas TRX has an anti-apoptotic effect by inhibiting apoptosis signal-regulating kinase 1 (ASK1). The activation of ASK1 and its downstream molecule, c-Jun N-terminal kinase, was observed after induction of TBP2 by CD437. Interestingly, CD437 induced the association of TBP2 with TRX and, in turn, facilitated the dissociation of ASK1 from TRX. Moreover, blockade of TBP2 induction by small interfering RNA (siRNA) significantly attenuated the cytotoxic effect of CD437. These results suggest that TBP2 plays a critical role in the mechanism by which CD437 exerts proapoptotic action against SKOV3 cells. (Cancer Sci 2008; 99: 2485,2490) [source] Monoamine oxidase A and B activities in embryonic chick hepatocytes: differential regulation by retinoic acidCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2002Antonietta Nicotra Abstract Monoamine oxidases (MAOs) A and B are two isoenzymes involved in the degradation of many biological amines in the nervous system and in peripheral organs. In the present work hepatocytes isolated from 14-day-old chick embryos were used as a model system to determine whether retinoic acid (RA) is capable of modulating the activity of the two MAO forms. RA is a retinoid that, by binding with nuclear receptors, interferes with the expression of specific genes in many differentiation processes. Enzymic activity was measured with a radiochemical method using serotonin and ,-phenylethylamine as preferential substrates for MAO A and MAO B, respectively. The specific activity of the two forms was measured in hepatocytes cultured for 24, 48 and 72,h in the presence and the absence of serum. RA stimulated MAO B but not MAO A activity, in a dose- and time-dependent way, and only in the presence of serum. Maximum stimulation (about 3.5-fold) was obtained after treatment with 5,,M RA for 72,h. Kinetic analysis of MAO B activity showed an increase in Vmax in treated hepatocytes (5,,M RA for 72,h) with no change in Km. In conclusion, the present work shows that RA selectively elicits MAO B activity in cultured chick embryonic hepatocytes, this stimulation requires the presence of some factors present in the serum and is probably due to an increase in the number of enzyme molecules. Copyright © 2001 John Wiley & Sons, Ltd. [source] Retinoids and Wound HealingDERMATOLOGIC SURGERY, Issue 10 2006MARK ABDELMALEK MD BACKGROUND Retinoids are widely used in dermatology and may play a role in wound healing. The exact role of retinoids in wounds is confusing and controversial, however. Systemic retinoids are presumed to be detrimental to wound healing; however, this standard is based on isolated reports. OBJECTIVE The objective was to provide a critical review of the available literature regarding the role of both topical and systemic retinoids in various aspects of wound healing. CONCLUSIONS Pretreatment with retinoids likely promotes wound healing after facial resurfacing procedures and full- or partial-thickness wounds. While the evidence is mixed regarding the effects of retinoids applied to fresh and healing wounds, the majority of the evidence available shows favorable wound-healing properties in this setting. The medical,legal standard regarding the avoidance of facial resurfacing and surgical procedures in patients on or recently completing a course of systemic retinoids was likely prematurely established. [source] Therapeutic Hotline: Treatment of prurigo nodularis and lichen simplex chronicus with gabapentinDERMATOLOGIC THERAPY, Issue 2 2010Gulsum Gencoglan ABSTRACT Psychocutaneous conditions are frequently encountered in dermatology practice. Prurigo nodularis and lichen simplex chronicus are two frustrating conditions that are classified in this category. They are often refractory to classical treatment with topical corticosteroids and antihistamines. Severe, generalized exacerbations require systemic therapy. Phototherapy, erythromycine, retinoids, cyclosporine, azathiopurine, naltrexone, and psychopharmacologic agents (pimozide, selective serotonin reuptake inhibitor antidepressants) were tried with some success. Here five cases with lichen simplex chronicus and four cases with prurigo nodularis, who responded well to gabapentin, are presented. [source] New and emerging treatments in dermatology: acneDERMATOLOGIC THERAPY, Issue 2 2008A. Katsambas ABSTRACT:, Topical retinoids, benzoyl peroxide, azelaic acid, and topical and oral antibiotics remain the milestone of treatment for mild to moderate acne vulgaris. Oral isotretinoin is useful for the treatment of severe nodular acne, treatment-resistant acne, and acne with a risk of physical or psychological scarring. Hormonal treatment in female acne is useful in resistant or late-onset acne. With increasing concerns regarding teratogenicity of isotretinoin and increasing antibiotic resistance, there is a clear need for therapeutic alternatives to these long-used treatments. Research in the pathogenesis of acne has allowed for new therapies and future perspectives regarding acne to evolve. They include low-dose long-term isotretinoin regimens, insulin-sensitizing agents, 5,-reductase type 1 inhibitors, topical photodynamic therapy, new combination formulations, dietary interventions, and antiinflammatory agents such as lipoxygenase inhibitors. [source] Skin lightening preparations and the hydroquinone controversyDERMATOLOGIC THERAPY, Issue 5 2007Zoe Diana Draelos ABSTRACT:, Skin lightening preparations are widely used in dermatology by persons of all Fitzpatrick skin types. Fitzpatrick skin types I,III require local pigment lightening for the treatment of hormonally induced melasma and postinflammatory hyperpigmentation caused by acne and trauma. Fitzpatrick skin types IV and darker have an even greater need for skin lightening for social reasons, as well as pigmentary changes that occur around the eyes, in the intertriginous areas, following dermatitis, or with acne and trauma. The gold standard dermatologic agent for skin lightening was hydroquinone, until regulatory agencies in Japan, Europe, and most recently in the United States questioned the safety of this substance. This has encouraged research into alternative agents to inhibit skin pigmentation such as retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N-acetyl glucosamine. The efficacy and safety of each of these ingredients is examined as possible topical alternatives to hydroquinone. [source] Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatologyDERMATOLOGIC THERAPY, Issue 5 2006Peter C. M. Van De Kerkhof ABSTRACT:, Both in the topical and systemic treatment of psoriasis, retinoids are mainstays. In this chapter the history and modes of actions of retinoids are presented. Tazarotene and acitretin are the only retinoids that are available in both topical and systemic formulations. A more extensive description of their pharmacology, modes of action, indications and contraindications, clinical results, and treatment strategies will be presented. Finally, retinoid X receptor ligands and retinoic acid metabolism blocking agents will be introduced as potential future retinoid mimetics in psoriasis. [source] | |||||||||||||||||||||||||||||||