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Doxycycline
Kinds of Doxycycline Terms modified by Doxycycline Selected AbstractsBiowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2010E. Jantratid Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for "very rapidly dissolving" or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are "rapidly dissolving.". © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1639,1653, 2010 [source] Quality of life in patients with facial steroid dermatitis before and after treatmentJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2008Z-H Liu Abstract Background, Improper long-term, even low-dose, topical corticosteroids, especially application to the face, could induce steroid dermatitis, which was refractory and detrimental to the quality of life. Objective, To evaluate the quality of life in patients with facial steroid dermatitis before and after the treatment of doxycycline and indomethacin plus support therapy. Study design, A prospective study. Setting, Outpatients of the Department of dermatology, the Third Hospital of Hangzhou, from August 2, 2004, to April 20, 2005. Subjects, Fifty consecutive outpatients completed the treatment. Intervention, The intervention is doxycycline 10 mg twice a day and indomethacin 25 mg twice a day for 4 weeks, cetirizine or loratadine 10 mg daily if pruritic, topical white petroleum if feeling dry and wet dressing if burning and oedema, plus psychological support and health education. Main outcome measure, The efficacy of the treatment was quantified using a 24-point steroid clinical score. The detriment of the quality of life was quantified using a 30-point Dermatology Life Quality Index. Results, The steroid dermatitis clinical score decreased significantly from 15.06 ± 4.61 at baseline to 4.52 ± 3.39 at 2 weeks after the end of treatment (week 6; P < 0.001). Twenty-one patients underwent a rebound phenomenon and the steroid dermatitis clinical score increased significantly from 13.71 ± 4.33 at baseline (week 0) to 19.24 ± 3.40 at 1 week after treatment (week 1; P < 0.001). Quality of life score decreased significantly from 13.76 ± 7.68 at baseline to 3.44 ± 2.57 at 2 weeks after the end of treatment (week 6; P < 0.001). Conclusions, The quality of life was profoundly affected by facial steroid dermatitis. Doxycycline and indomethacin plus support therapy might be effective in patients with facial steroid dermatitis. [source] Pharmacokinetics of pradofloxacin and doxycycline in serum, saliva, and tear fluid of cats after oral administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008A. HARTMANN The pharmacokinetic properties of pradofloxacin and doxycycline were investigated in serum, saliva, and tear fluid of cats. In a crossover study design, six cats were treated orally with a single dose of pradofloxacin (Veraflox® Oral Suspension 2.5%) and doxycycline (Ronaxan® 100 mg) at 5 mg/kg body weight. Following administration, samples of serum, saliva, and tear fluid were taken in regular intervals over a period of 24 h and analysed by turbulent flow chromatography/tandem mass spectrometry. All values are given as mean ± SD. Pradofloxacin reached a mean maximum serum concentration (Cmax) of 1.1 ± 0.5 ,g/mL after 1.8 ± 1.3 h (tmax). In saliva and tear fluid, mean Cmax was 6.3 ± 7.0 and 13.4 ± 20.9 ,g/mL, respectively, and mean tmax was 0.5 ± 0 and 0.8 ± 0.3 h, respectively. Doxycycline reached a mean Cmax in serum of 4.0 ± 0.8 ,g/mL after 4.3 ± 3.2 h. Whilst only at two time-points doxycycline concentrations close to the limit of quantification were determined in tear fluid, no detectable levels were found in saliva. The high concentrations of pradofloxacin in saliva and tear fluid are promising to apply pradofloxacin for the treatment of conjunctivitis and upper respiratory tract infections in cats. As doxycycline is barely secreted into these fluids after oral application the mechanisms of its clinical efficacy remain unclear. [source] Pharmacokinetics of oral doxycycline and concentrations in body fluids and bronchoalveolar cells of foalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2007A. WOMBLE The objective of this study was to determine the disposition of orally administered doxycycline in foals. Six healthy 4- to 8-week-old foals were used. Doxycycline was administered to each foal via the intragastric (IG) route at dosages of 10 and 20 mg/kg, in a cross-over design. After the first 10 mg/kg dose, five additional doses were administered at 12-h intervals. A microbiological assay was used to measure doxycycline activity in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal (CSF), pulmonary epithelial lining fluid (PELF), and bronchoalveolar (BAL) cells. Following administration at 10 mg/kg, mean ± SD time to peak serum doxycycline activity (tmax) was 3.0 ± 1.2 h, maximum serum activity (Cmax) was 2.54 ± 0.27 ,g/mL, and terminal half-life (t1/2) was 8.5 ± 2.8 h. Administration at a dose of 20 mg/kg resulted in a significantly longer tmax (5.5 ± 1.8 h) as well as a tendency toward higher Cmax (2.89 ± 0.33 ,g/mL) and longer t1/2 (11.9 ± 2.6 h). After multiple IG doses, doxycycline activity in CSF was significantly lower than concurrent serum activity, whereas peritoneal fluid, synovial fluid, and BAL cell doxycycline activity was similar to concurrent serum activity. Doxycycline activity in urine and PELF was significantly higher than that found at other sites. Oral administration at a dosage of 10 mg/kg every 12 h would maintain serum, PELF, and BAL cell activity above the minimum inhibitory concentrations of Rhodococcus equi, , -hemolytic streptococci, and other susceptible bacterial pathogens for the entire dosing interval. [source] Pathology is alleviated by doxycycline in a laminin-,2,null model of congenital muscular dystrophyANNALS OF NEUROLOGY, Issue 1 2009Mahasweta Girgenrath PhD Objective Congenital muscular dystrophy type 1A is an autosomal recessive disease that is caused by loss-of-function mutations in the laminin-,2 gene, and results in motor nerve and skeletal muscle dysfunction. In a previous study, we used genetic modifications to show that inappropriate induction of apoptosis was a significant contributor to pathogenesis in a laminin-,2,deficient mouse model of congenital muscular dystrophy type 1A. To identify a possible pharmacological therapy for laminin-,2 deficiency, we designed this study to determine whether treatment with minocycline or doxycycline, which are tetracycline derivatives reported to have antiapoptotic effects in mammals, would significantly increase lifespan and improve neuromuscular function in laminin-,2,deficient mice. Methods Mice that were homozygous for a targeted, inactivating mutation of the laminin-,2 gene were placed into control, minocycline-treated, or doxycycline-treated groups. Drug treatment began within 2 weeks of birth, and the progression of disease was followed over time using behavioral, growth, histological, and molecular assays. Results We found that treatment with either minocycline or doxycycline increased the median lifespan of laminin-,2,null mice from approximately 32 days to approximately 70 days. Furthermore, doxycycline improved postnatal growth rate and delayed the onset of hind-limb paralysis. Doxycycline-treated laminin-,2,deficient muscles had increased Akt phosphorylation, decreased inflammation, and decreased levels of Bax protein, terminal deoxynucleotidyltransferase,mediated dUTP nick end labeling,positive myonuclei, and activated caspase-3. Interpretation Doxycycline or other drugs with similar functional profiles may be a possible route to improving neuromuscular dysfunction caused by laminin-,2-deficiency. Ann Neurol 2008 [source] Doxycycline-induced staining of permanent adult dentitionAUSTRALIAN DENTAL JOURNAL, Issue 4 2005E. Ayaslioglu Abstract Background: Doxycycline is the most effective antibiotic for managing brucellosis. Although it is relatively free from side effects, complications involving the skin, nails and teeth may rarely be encountered. Methods: Four patients with brucellosis developed yellow-brown discolouration of teeth following a 30,45 day course of doxycycline therapy during summer at a dose of 200mg/day. Results: All four patients were diagnosed as having doxycycline-induced staining of the permanent dentition. In all cases, the staining completely resolved and the teeth recovered their original colour following abrasive dental cleaning. Conclusions: These observations indicate that the incidence of staining of the permanent dentition, as a complication of doxycycline, may be much higher than the literature indicates, especially if treatment is administered during summer months. Fortunately, this complication is reversible and does not require termination of doxycycline therapy. Complete resolution following abrasive cleaning may suggest that an extrinsic mechanism within the dental milieu may be involved in its pathogenesis. Strict avoidance of sunlight exposure during high-dose, long-term doxycycline therapy might prevent the development of this complication. [source] Removal of intracanal smear layer by doxycycline: SEM analysisAUSTRALIAN ENDODONTIC JOURNAL, Issue 2 2010Mara Cristina Santos felippe Abstract The aim of this study was to verify the efficacy of doxycycline used alone or in association with sodium hypochlorite on smear layer removal. The canals of extracted human teeth were instrumented using a stepback technique. At the end of preparation, they were irrigated with doxycycline (Group 1), ethylenediaminetetraacetic acid + sodium hypochlorite (Group 2), doxycycline + sodium hypochlorite (Group 3) and water (Group 4). The dentinal wall of the cervical, middle and apical thirds was graded according to the amount of remaining debris and smear layer. The results were analysed using the Kruskal,Wallis test (P < 0.05). In Groups 2 and 4, the dentine was completely free and covered with smear layer, respectively. The results from the cervical and middle thirds of Group 3 were worse than those in Groups 1 and 2 (P < 0.05). In relation to apical third, there were differences (P < 0.05) between all groups with best results for Group 2. Doxycycline was effective in removing smear layer from cervical and middle thirds. The use of doxycycline + sodium hypochlorite was partially effective in the cervical and middle thirds, but ineffective in the apical third. [source] Pulp revascularization of replanted immature dog teeth after treatment with minocycline and doxycycline assessed by laser Doppler flowmetry, radiography, and histologyDENTAL TRAUMATOLOGY, Issue 2 2004Alessandra Luisa de Souza Ritter Abstract,,, This study investigated the effect of topical antibiotic treatment on pulp revascularization in replanted teeth. Thirty-four immature teeth were selected from three young dogs. Baseline radiographs and laser Doppler flowmetry (LDF) readings were obtained. Specimens were randomly divided into four groups: Thirty-eight teeth were extracted, kept dry for 5 min, and either (Group 1) covered with minocycline mixture (G1, n = 11), (Group 2) soaked in doxycycline (G2, n = 11), or (Group 3) soaked in saline (G3-negative control, n = 6), and replanted. Teeth in Group 4 were not extracted (positive control, n = 6). Postoperative radiographs and LDF readings were obtained for 2 months after replantation. After sacrifice, the jaws were collected and processed for light microscopy. Pre- and postreplantation LDF readings and radiographs, and histologic findings were analyzed to assess revascularization. Pulp revascularization occurred in 91% (G1), 73% (G2), and 33% (G3) of the specimens. In conclusion, minocycline facilitates pulp revascularization in replanted immature teeth after replantation. [source] Pulp revascularization of replanted immature dog teeth after different treatment methodsDENTAL TRAUMATOLOGY, Issue 5 2000K. Yanpiset Abstract , The purpose of the present study was to determine the effect of topical treatment with doxycycline and/or the application of unfilled resin to the anatomical crown on the occurrence of revascularization in reimplanted dog teeth. Ninety-six teeth in 4 young mongrel dogs were used. Eighty one teeth were atraumatically extracted and divided into four groups. Group 1, 17 teeth were kept dry for 5 min and then replanted. Group 2, 21 teeth were soaked with a freshly prepared solution of doxycycline (1 mg/20 mL saline) for 5 min before replantation. Group 3, 23 teeth were soaked with the doxycycline solution for 5 min, and then replanted. The crowns were coated with 2 layers of light cured unfilled resin. Group 4, 20 teeth were kept dry for 5 min, and then replanted. The crowns were treated as with the teeth in Group 3. Three months after surgery, radiographic evaluation revealed that 27 teeth had continued root development and 32 teeth showed arrested root development with periradicular pathosis. The remaining 17 teeth, which had arrested root development but no signs of periradicular pathosis, were all histologically evaluated for final assessment. The occurrence of revascularization according to treatment group was 29.4%, 60%, 60%, 36.8% in Group 1, 2, 3, and 4, respectively. A multiple logistic regression analysis in SAS indicated there was no significant association between vitality and dog (P=0.7564). Soaking for 5 min in doxycycline significantly increased the revascularization rate (P=0.024) while the addition of resin to the crown did not result in an increased incidence of pulp revascularization (P=0.823). [source] Conditional expression of a myocardium-specific transgene in zebrafish transgenic linesDEVELOPMENTAL DYNAMICS, Issue 4 2005Chiu-Ju Huang Abstract To develop the first heart-specific tetracycline (Tet)-On system in zebrafish, we constructed plasmids in which the cardiac myosin light chain 2 promoter of zebrafish was used to drive the reverse Tet-controlled transactivator (rtTA) and the green fluorescent protein (GFP) reporter gene was preceded by an rtTA-responsive element. In the zebrafish fibroblast cell-line, rtTA-M2, one of rtTA's derivatives, demonstrated the highest increase in luciferase activity upon doxycycline (Dox) induction. We then generated two germ lines of transgenic zebrafish: line T03 was derived from microinjection of a plasmid containing rtTA-M2 and a plasmid containing a responsive reporter gene, whereas line T21 was derived from microinjection of a single dual plasmid. Results showed that line T21 was superior to line T03 in terms of greater GFP intensity after induction and with of minimal leakiness before induction. The photographic images of induced GFP in the heart of F2 larvae showed that the fluorescent level of GFP was dose-responsive. The level of GFP expressed in the F3 3 days postfertilization larvae that were treated with Dox for 1 hr decreased gradually after the withdrawal of the inducer; and the fluorescent signal disappeared after 5 days. The GFP induction and reduction were also tightly controlled by Dox in the F3 adult fish from line T21. This Tet-On system developed in zebrafish shows much promise for the study of the gene function in a specific tissue at the later developmental stage. Developmental Dynamics 233:1294,1303, 2005. © 2005 Wiley-Liss, Inc. [source] Characterization of interaction between doxycycline and human serum albumin by capillary electrophoresis-frontal analysisELECTROPHORESIS, Issue 11 2009Hanwen Sun Abstract The binding of doxycycline to HSA under simulated physiological conditions (pH 7.4, 67,mM phosphate, I=0.17, drug concentration 100,,M, HSA concentration up to 475,,M, 36.5°C) was studied by CE-frontal analysis. The number of primary binding sites, binding constant and physiological protein-binding percentage were 1.9, 1.51×103,M,1 and 59.80%, respectively. In addition, the thermodynamic parameters including enthalpy change (,H), entropy change (,S) and free energy change (,G) of the reaction were obtained in order to characterize the acting forces between doxycycline and HSA. Furthermore, to better understand the nature of doxycycline,HSA binding and to get information about potential interaction with other drugs, displacement experiments were performed. The results showed that doxycycline binds at site II of HSA. [source] SPE and large-volume sample stacking in MEKC for determination of doxycycline in biological fluids: Comparison of direct injection to SPE-MEKCELECTROPHORESIS, Issue 21 2008Rade Injac Abstract A novel and simple method has been developed for the determination of doxycycline (DOX) in biological fluids. The method is based on SPE, large-volume sample stacking (LVSS) and MEKC with UV-DAD detection. Six SPE cartridges have been used in investigation for sample clean up and pre-concentration (Supelco® LC-8, LC-18, LC-SCX, and LC-WCX, as well as StrataÔ-X and X-C). DOX was determined on a 56,cm (effective length 50,cm)×50,,m id fused-silica capillary. The BGE was 20,mM borate buffer, pH 9.3, containing 80,mM SDS and 7.5%,v/v of methanol (30,s×50,mbar), and the temperature and voltage were 25°C and 30,kV, respectively. The analytical wavelength was set at 210,nm. Under optimized conditions it is possible to determine DOX in human serum, urine, semen, tears and saliva with recovery of 97.5% (RSD 2.5%). The method was shown to be sensitive (LOD is 1,,g/L) and precise (intra-day RSD 0.2 and 2.4%; inter-days 0.4 and 3.5% for migration time and peak area, respectively). Results for developed SPE-LVSS-MEKC were compared with LVSS-MEKC method with direct sample injection. The new LVSS-MEKC method is presented as a useful technique for rapid determination without extraction procedure of DOX in human urine and serum, using 80,mM of SDS, 10%,v/v of methanol and 40,mM borate buffer (pH 9.3; 30,s×50,mbar; 25°C; 30,kV; 350,nm), but not for the other biological fluids, according to lower sensitivity of the method and because of the sample composition. [source] Silencing dopamine D3 -receptors in the nucleus accumbens shell in vivo induces changes in cocaine-induced hyperlocomotionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2005Amine Bahi Abstract The dopamine D3 receptor (D3R) is an important pharmacotherapeutic target for its potential role in psychiatric disorders and drug dependence. To further explore its function in rats, a regulatable lentivirus, Lenti-D3, holding the rat D3R cDNA, has been constructed as well as three nonregulatable lentiviruses, Lenti-D3-siRNA1, Lenti-D3-siRNA2 and Lenti-D3-siRNA3, expressing small hairpin RNAs, aimed at silencing D3R expression and specifically targeted against different regions of the D3R mRNA. In vitro, Lenti-D3 expressed D3R and could efficiently be blocked with Lenti-D3-Sils. These viruses were stereotaxically injected into the shell part of the nucleus accumbens (NAcc) and effects of passive cocaine delivery on locomotor activity were assessed. Manipulations of D3R levels induced changes in the locomotor stimulant effects of cocaine as compared to control treatment. Suppression of dopamine (DA) D3R in the NAcc by means of local knockdown (with Lenti-D3-Sils) increased locomotor stimulant effects, whereas its overexpression with Lenti-D3 drastically reduced them. The latter effects could be reversed when animals were fed doxycycline, which prevented lentiviral-mediated DA D3R overexpression in the NAcc. Gene expression assessed by quantitative RT-PCR confirmed very efficient gene knockdown in vivo in animals treated with Lenti-D3-Sils (> 93% silencing of D3R gene). Thus D3R expression significantly contributes to behavioural changes associated with chronic cocaine delivery. [source] Fast set-up of doxycycline-inducible protein expression in human cell lines with a single plasmid based on Epstein,Barr virus replication and the simple tetracycline repressorFEBS JOURNAL, Issue 3 2007Markus Bach We have developed a novel plasmid vector, pEBTetD, for full establishment of doxycycline-inducible protein expression by just a single transfection. pEBTetD contains an Epstein,Barr virus origin of replication for stable and efficient episomal propagation in human cell lines, a cassette for continuous expression of the simple tetracycline repressor, and a cytomegalovirus-type 2 tetracycline operator (tetO2)-tetO2 promoter. As there is no integration of vector into the genome, clonal isolation of transfected cells is not necessary. Cells are thus ready for use 1 week after transfection; this contrasts with 3,12 weeks for other systems. Adequate regulation of protein expression was accomplished by abrogation of mRNA polyadenylation. In northern analysis of seven cDNAs coding for transport proteins, pools of transfected human embryonic kidney 293 cells showed on/off mRNA ratios in the order of 100 : 1. Cell pools were also analyzed for regulation of protein function. With two transport proteins of the plasma membrane, the on/off activity ratios were 24 : 1 and 34 : 1, respectively. With enhanced green fluorescent protein, a 23 : 1 ratio was observed based on fluorescence intensity data from flow cytometry. The unique advantage of our system rests on the unmodified tetracycline repressor, which is less likely, by relocation upon binding of doxycycline, to cause cellular disturbances than chimera of tetracycline repressor and eukaryotic transactivation domains. Thus, in a comprehensive comparison of on- and off-states, a steady cellular background is provided. Finally, in contrast to a system based on Flp recombinase, the set-up of our system is inherently reliable. [source] Fluctuation of chromatin unfolding associated with variation in the level of gene expressionGENES TO CELLS, Issue 7 2004Noriko Sato We examined whether spontaneous alteration of chromatin structure, if any, correlates with variation in gene expression. Gene activation is associated with changes in chromatin structure at different levels. Large-scale chromatin unfolding is one such change detectable under the light microscope. We established cell clones carrying tandem repeats (more than 50 copies spanning several hundred kb) of the GFP (green fluorescent protein)-ASK reporter genes driven by a tetracycline responsive promoter. These clones constitutively express the transcriptional transactivator. Flow cytometry and live-recording fluorescence microscopy revealed that, although fully activated by a saturating amount of doxycycline, GFP-ASK expression fluctuated in individual cell clones, regardless of the cell cycle stage. The GFP-ASK expression changed from lower to higher levels and vice versa within a few cell cycles. Furthermore, the levels of GFP-ASK expression were correlated with the degrees of chromatin unfolding of the integrated array as detected by FISH (fluorescent in situ hybridization). The chromatin unfolding was not coupled to a mitotic event; around one-third of the daughter-pairs exhibited dissimilar degrees of chromatin unfolding. We concluded that fluctuation of chromatin unfolding was likely to result in variation in gene expression, although the source of the fluctuation of chromatin unfolding remains to be studied. [source] Construction and characterization of a doxycycline-inducible transgenic system in Msx2 expressing cellsGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 5 2009Congxing Lin Abstract Homeobox gene Msx2 is widely expressed during both embryogenesis and postnatal development and plays important roles during organogenesis. We developed an Msx2 -rtTA BAC transgenic line which can activate TetO-Cre expression in Msx2 -expressing cells upon doxycycline (Dox) treatment. Using the Rosa26-LacZ (R26R) reporter line, we show that rtTA is activated in Msx2 -expressing organs including the limb, heart, external genitalia, urogenital system, hair follicles and craniofacial regions. Moreover, we show that in body appendages, the transgene can be activated in different domains depending on the timing of Dox treatment. In addition, the transgene can also be effectively activated in adult tissues such as the hair follicle and the urogenital system. Taken together, this Msx2 -rtTA;TetO-Cre system is a valuable tool for studying gene function in the development of the aforementioned organs in a temporal and spatially-restricted manner, as well as for tissue lineage tracing of Msx2 -expressing cells. When induced postnatally, this system can also be used to study gene function in adult tissues without compromising normal development and patterning. genesis 47:352,359, 2009. © 2009 Wiley-Liss, Inc. [source] Inducible gene expression with the Tet-on system in CD4+ T cells and thymocytes of miceGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 7 2007Jisen Huai Abstract CD4+ T cells with their growing list of effector and regulatory subpopulations have vital functions within the immunohematopoietic system. We report here on the first mouse lines that allow temporally and quantitatively controlled expression of transgenes specifically in CD4+ thymocytes and T cells. These were constructed using the Tet-on system. The rtTA2S -M2 version of the reverse tetracycline-dependent transactivator was placed under control of all known CD4 regulatory elements. Reporter transgene expression in mice expressing these constructs is highly specific for CD4+ cells, is strictly dependent on the tetracycline derivative doxycycline, and can be regulated by up to five logs depending on the doxycycline concentration. Moreover, we demonstrate that these mice can be used for noninvasive in vivo imaging of a coexpressed luciferase reporter. These new mouse lines should be highly valuable for studying and manipulating numerous aspects of CD4+ T cell development, biology, and function. genesis 45:427,431, 2007. © 2007 Wiley-Liss, Inc. [source] Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclinesGLIA, Issue 8 2006Aaron Y. Lai Abstract The tetracycline derivatives minocycline (MINO) and doxycycline (DOXY) have been shown to be neuroprotective in in vivo and in vitro models of stroke. This neuroprotection is thought to be due to the suppression of microglial activation. However, the specific molecular parameters in microglia of the tetracyclines' effect are not understood. We subjected cultured rat microglial and neuronal cells to in vitro hypoxia and examined the effects of MINO and DOXY pre-treatments. Our data showed that MINO and DOXY protect against hypoxia-induced neuronal death by a mechanism dependent on regulation of microglial factors, but likely unrelated to regulation of microglial proliferation/viability. Both MINO and DOXY suppressed the hypoxic activation of ED-1, a marker for microglial activation. Morphological analyses of hypoxic microglia using the microglial marker Iba1 revealed that treatment with MINO and DOXY caused a higher percentage of microglia to remain in a non-activated state. MINO suppressed the hypoxic upregulation of pro-inflammatory agents nitric oxide (NO), interleukin-1 beta (IL-1,), and tumor necrosis factor alpha (TNF-,), while DOXY down-regulated only NO and IL-1,. In contrast, the hypoxic activation of pro-survival/neuroprotective microglial proteins, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), were unaffected by tetracycline treatments. Taken together, these results suggest that MINO and DOXY may provide neuroprotection against stroke by selectively down-regulating microglial toxic factors while maintaining functional pro-survival factors. © 2006 Wiley-Liss, Inc. [source] Failure of Helicobacter pylori Treatment After Regimes Containing Clarithromycin: New Practical Therapeutic OptionsHELICOBACTER, Issue 6 2008Bruno Sanches Abstract Failure of Helicobacter pylori treatment is a growing problem in daily practice. Aim:, To evaluate the efficacy of two new regimes as second-line options in a randomized and prospective study. Methods:, Patients in whom a first eradication regime containing clarithromycin had failed were included. After performing gastroscopy and a 13C-urea breath test (UBT), the patients were randomized to receive a combination of 20 mg of rabeprazole, 500 mg of levofloxacin, and 200 mg (two tablets) of furazolidone administered once daily for 10 days (RLF) or the combination of 20 mg of rabeprazole, 120 mg (two tablets) of bismuth subcitrate, 100 mg of doxycycline, and 200 mg of furazolidone, administered twice daily for 10 days (RBDF). Clinical examinations and new UBT were performed 60 days after therapy. Results:, Sixty patients were included (mean age, 46 years, 57% females). Two patients were excluded: one because of adverse effects and another as a result of protocol violation. Compliance was similar in both groups (90% took all medications correctly). Side-effects (96% mild) were observed in 87% of the patients and were comparable between groups, except diarrhea, which was more frequent in group RLF (p= .025). Intention-to-treat cure rates were 77% (95% confidence interval (CI): 62,93%) in the RLF group and 83% (95% CI: 68,97%) in the RBDF group (p= .750). Per-protocol cure rates were 80% (95% CI: 65,95%) in the RLF group and 82% (95% CI: 67,96%) in the RBDF group (p= 1.0). Conclusions:, Both once-daily triple (rabeprazole, levofloxacin, and furazolidone) and twice-daily quadruple therapy (rabeprazole, bismuth subcitrate, doxycycline, and furazolidone) for 10 days achieved encouraging results. Subsequent studies should be performed to evaluate antibiotic resistance, doses, dosing intervals, duration of treatment, and safety of these two regimes. [source] Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug-induced steatosis in miceHEPATOLOGY, Issue 1 2003Philippe Lettéron Although many steatogenic drugs inhibit mitochondrial fatty acid ,-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial ,-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on ,-oxidation or only MTP. [source] Increased plasma MMP9 in integrin ,1-null mice enhances lung metastasis of colon carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Xiwu Chen Abstract Inhibitors of matrix metalloproteinases (MMPs) were developed as anticancer agents based on the observation that MMPs facilitate local tumor spread and metastasis by promoting matrix degradation and cell migration. Unfortunately, these inhibitors were unsuccessful in the clinical treatment of several cancers, including lung cancer. A possible reason contributing to their failure is that MMP activity is critical for the generation of inhibitors of tumor angiogenesis, including angiostatin. Thus, MMPs might play opposing roles in tumor vascularization and invasion. To determine which effect of elevated MMP levels dominates in the progression of metastatic cancer, experimental lung metastasis assays were performed in integrin ,1-null mice, a genetic model for increased plasma levels of MMP9 and MMP9-generated angiostatin (Pozzi et al., Proc. Natl. Acad. Sci. USA 2000;97:2202,7). We show that while the number of lung colonies in integrin ,1-null mice was significantly increased compared to their wild-type counterparts, tumor volume was markedly reduced. In vivo treatment with the MMP inhibitor doxycycline resulted in a significant decrease in the number of lung colonies in both genotypes, but the tumors that formed were bigger and more vascularized. Increased tumor vascularization paralleled decreased plasma levels of MMP9 and consequent decreased angiostatin synthesis. These results demonstrate that while inhibition of MMPs prevents and/or reduces tumor invasion and lung metastasis, it has the paradoxical effect of increasing the size and vascularization of metastatic tumors due to decreased generation of inhibitors of endothelial cell proliferation. The continued growth of these large well-vascularized tumors may explain the poor efficacy of MMP inhibitors in lung cancer clinical trials. © 2005 Wiley-Liss, Inc. [source] Post-treatment effects of subantimicrobial dose doxycycline on clinical parameters and gingival crevicular fluid transforming growth factor-,1 in severe, generalized chronic periodontitisINTERNATIONAL JOURNAL OF DENTAL HYGIENE, Issue 2 2008A Gürkan Abstract:, Objective:, Present study aimed to evaluate the effect of 3-month adjunctive subantimicrobial dose doxycycline (SDD) on clinical parameters and gingival crevicular fluid (GCF) transforming growth factor-beta1 (TGF-,1) levels in chronic periodontitis patients over 12 months. Methods:, Thirty-five patients with severe, generalized periodontitis participated in the present randomized, placebo-controlled study. Patients received scaling and root planing (SRP) plus 3 months adjunctive SDD or placebo. Clinical measurements and GCF sampling were performed at baseline, 3, 6, 9 and 12 months. Eleven periodontally healthy subjects served as controls for GCF TGF-,1 analysis. Results:, Clinical parameters of both SDD and placebo groups significantly improved during the study (P < 0.0125). SDD group exhibited significantly higher PD reduction at deep sites (baseline PD ,7 mm) compared with placebo group at 6 months (P < 0.05). In SDD group significantly higher percentage of deep pockets resolved (PD reduction ,3 mm from baseline) when compared with placebo group at 6 and 9 months (73.4% versus 49.7%; 79.9% versus 50.6%, respectively, P < 0.05). PD reduction ,4 mm for deep pockets from baseline was also greater in SDD group than placebo at 6 months (53.4% versus 36.3%, P < 0.05). GCF TGF-,1 levels of SDD group was significantly higher than baseline (P < 0.0125) and placebo group (P < 0.017) at 3 months. Conclusions:, These results ensure further data for beneficial effects of adjunctive SDD therapy in the management of severe chronic periodontitis. [source] Comparison of efficacy of azithromycin vs. doxycycline in the treatment of rosacea: a randomized open clinical trialINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 3 2008Maryam Akhyani MD Background, Rosacea is a common inflammatory disorder of the skin. Systemic antibiotics currently used in the treatment of rosacea are sometimes associated with uncomfortable side effects. Therefore, a need for an effective agent with few side effects and good patient compliance exists. Azithromycin, a macrolide antibiotic with prolonged mode of action, has recently been found to be an effective alternative in the treatment of inflammatory acne. Methods, For evaluation of the efficacy of azithromycin in the treatment of rosacea, we planned a randomized, open, clinical trial study to compare the efficacy of azithromycin with doxycycline in the treatment of this disease. Sixty-seven patients were randomized to receive either azithromycin 500 mg thrice weekly (on Monday, Wednesday, and Saturday) in the first, 250 mg thrice weekly (on Monday, Wednesday, and Saturday) in the second, and 250 mg twice weekly (on Tuesday, and Saturday) in the third month. The other group was given doxycycline 100 mg/day for the three months. Clinical assessment was made at baseline, at the end of first, second, third, and 2 months after treatment. Side affects were recorded. The limitation of this study is that there was no blindness. Results, Statistically significant improvement was obtained with both drugs. Neither drug was shown to be more effective than the other. In the azithromycin group four patients had diarrhea, while epigastric burning was seen in two patients using doxycycline. Conclusion, This study indicates that azithromycin is at least as effective as doxycycline in the treatment of rosacea. [source] Tetracycline/doxycycline-induced cutaneous depressed pigmentationINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 10 2006Esra Adisen MD Pigmentary disorders are recognized adverse effects of tetracyclines. Unlike minocycline, which occasionally causes black pigmentation of a variety of tissues, tetracycline itself or doxycycline is rarely attributed to the pigmentation of skin. Herein, we report the first case report of blue-black discoloration developed within depressed acne scars following tetracycline/doxycycline therapy for acne. [source] Evaluation of a magnetic resonance biomarker of osteoarthritis disease progression: doxycycline slows tibial cartilage loss in the Dunkin Hartley guinea pigINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2009Jonathan Bowyer Summary The objective was to assess the effect of doxycycline treatment on a magnetic resonance imaging (MRI) biomarker of cartilage volume loss, and on matrix metalloproteinase (MMP) activity in a guinea pig osteoarthritis model. Guinea pigs (9 months old) were dosed with vehicle or doxycycline, 0.6, 3.0 mg/kg/day for 66 days. Fat-suppressed 3D gradient-echo MRI of the left knee was acquired pre- and post dosing. Change in medial tibial plateau (MTP) cartilage volume (MT.VC) was determined using image analysis. At termination, MTP cartilage was removed from knees and proteolytic MMP activity determined using a fluorescent peptide substrate assay. Vehicle-treated animals lost 20.5% (95% CI mean 25.6,15.1) MT.VC. The doxycycline (0.6 mg/kg/day) group lost 8.6% (P < 0.05, 95% CI 20.6 to ,5.3) whilst the 3.0 mg/kg/day group lost 10.0% (P < 0.05, 95% CI 13.9,6.0%). Endogenous levels of active MMPs were below limits of detection in all samples. However, doxycycline treatment ablated amino phenyl mercuric acid activated MMP-13 and MMP-8 levels, reduced MMP-9 levels by 65% and MMP-1 levels by 24%. Doxycycline treatment resulted in partial protection from MT.VC loss and was associated with complete reduction in MMP-13 and MMP-8, and partial reduction in MMP-9 activity. These data imply a role of MMPs in cartilage degeneration but incomplete protection suggests that additional doxycycline insensitive mechanisms are important in this model. The protective effect of doxycycline correlates with the clinical finding of lessened joint space narrowing, strengthens the utility of this animal model in identifying disease-modifying osteoarthritic drugs and supports the use of MRI biomarkers of cartilage loss. [source] African tick bite fever , Papulovesicular exanthem with fever after staying in South AfricaJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 5 2008Jan Schuster Summary In the wake of expanding international tourism, rickettsioses are increasingly observed also in central Europe. African tick bite fever is a recently described, acute febrile illness with characteristic skin lesions. It is caused by Rickettsia africae, which is transmitted to humans by ticks of the Amblyomma genus. A 60-year-old woman presented with a papulovesic-ular exanthem, fever, and headache after returning from South Africa. A purple nodule with central necrosis ("tache noire"or "inoculation eschar") was noticed on the lower leg. Antibodies against rickettsia of the spotted fever group were detected serologically. Oral doxycycline led to clearance of the disease after few days of treatment. [source] Membranes of cellulose triacetate produced from sugarcane bagasse cellulose as alternative matrices for doxycycline incorporationJOURNAL OF APPLIED POLYMER SCIENCE, Issue 6 2009Guimes Rodrigues Filho Abstract Cellulose triacetate (CTA) membranes were prepared using polyethylene glycol, 600 g mol,1, (PEG) as additive and were utilized in essays of doxycycline (DOX) incorporation using two different procedures: (i) incorporation of the drug during the membrane preparation and (ii) incorporation of the drug to a previously prepared membrane. In the first, the produced membrane presented high compatibility between DOX and CTA, what was evidenced by analyzing the DSC curve for a CTA/PEG 50%/DOX system. Results showed that the drug is homogeneously distributed throughout the matrix, molecularly. In the second method, the drug was molecularly and superficially adsorbed, as seen through the DSC curve for the system CTA/PEG 10%/DOX, which nearly does not present alterations in relation to the original material, and through the isotherm of drug adsorption that follows the Langmuir model. Results showed that the membranes produced from sugarcane bagasse are adequate to produce matrices for drug-controlled release, both for enteric use (Method (i)) and topic use (Method (ii)). © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009 [source] Microencapsulation of doxycycline into poly(lactide- co -glycolide) by spray drying technique: Effect of polymer molecular weight on process parametersJOURNAL OF APPLIED POLYMER SCIENCE, Issue 6 2008Pradip Patel Abstract Poly(lactide- co -glycolide) (PLGA) polymers with three different molecular weights were prepared, and microparticles were produced by spray drying and water-in-oil-water (w/o/w) double emulsion techniques to encapsulate 86% of doxycycline (DXY), an antibiotic drug, for the use of periodontitis. Placebo and drug-loaded microspheres and pristine DXY were analyzed by Fourier transform infrared spectroscopy, which indicated no chemical interactions between DXY and PLGA. X-ray diffraction of drug-loaded microspheres confirmed the molecular level dispersion of DXY in PLGA. Scanning electron microscopy confirmed spherical nature and smooth surfaces of the microspheres. Mean particle size as measured by laser light scattering technique ranged between 10 and 25 ,m. In vitro release of DXY performed in 7.4 pH media continued up to 72 h and depended on molecular weight of PLGA and extent of DXY loading. Antimicrobial studies performed on one formulation and placebo microspheres suggested that drug concentrations during in vitro release are above the minimum inhibitory concentration (MIC) for Staphylococcus aureus growth. Overall, the release studies depended on the molecular weight of PLGA, extent of drug loading, and the method used to prepare microspheres. Statistical analyses of release data performed using the analysis of variance (ANOVA) method agreed well with experimental observations. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source] Etiology and Management of Chylothorax Following Pediatric Heart SurgeryJOURNAL OF CARDIAC SURGERY, Issue 4 2009Michael Milonakis M.D. The purpose of this study was to review our experience with the management of chylothorax following congenital heart surgery. Methods: Between September 1997 and August 2006, of 1341 pediatric patients undergoing correction of congenital heart disease in our institution, 18 (1.3%) developed chylothorax postoperatively. Surgical procedures included tetralogy of Fallot repair in 10 patients, ventricular septal defect closure (one), atrial septal defect with pulmonary stenosis repair (one), Fontan procedure (three), coarctation of the aorta repair (one), aortopulmonary shunt (one), and ligation of patent ductus arteriosus in one patient. All patients followed a therapeutic protocol including complete drainage of chyle collection and controlled nutrition. Somatostatin was used adjunctively in six (33.3%) patients. Surgical intervention was reserved for persistent lymph leak despite maximal therapy. Following resolution of chylothorax, a medium-chain triglyceride diet was implemented for six weeks. Results: There were no deaths. Fifteen patients (83.3%) responded to conservative therapy. Lymph leak ranged from 2.5 to 14.7 mL/kg per day for 8 to 42 days. Three patients with persistent drainage required thoracotomy with pleurodesis to achieve resolution, in two of which previously attempted chemical pleurodesis with doxycycline proved ineffective. Duration of lymph leak in this subgroup ranged from 15 to 47 days with 5.1 to 7.4 mL/kg per day output. Conclusions: Postoperative chylothorax is an infrequent complication of surgery for congenital heart disease and can occur even after median sternotomy in the absence of pathologically elevated venous pressure or Fontan circulation. Although hospitalization can be prolonged, conservative therapy is effective in most cases, while surgical pleurodesis proved successful in the refractory cases. [source] Inducible expression of a MAP kinase phosphatase-3-GFP chimera specifically blunts fibroblast growth and ras-dependent tumor formation in nude mice,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2004S. Marchetti The p42/p44 mitogen activated protein kinase (MAPK) pathway participates in a wide range of cellular programs including proliferation, migration, differentiation, and survival. Specific pharmacological inhibitors, like PD98059 and U0126, are often used to inhibit p42/p44 MAPK signaling. However, these inhibitors are not appropriate to study the function of these kinases in whole organisms. We thus developed an inducible system designed to inhibit p42/p44 MAPK activity through the expression of a phosphatase specific for these two kinases, the MAPK phosphatase 3 (MKP-3). A fibroblast cell line was established in which MKP-3 expression is controlled by tetracycline. Tetracycline-induced MKP-3 resulted in partial de-phosphorylation of p42/p44 MAPKs in serum-stimulated cells. However, we could improve MKP-3 stability and thereby the rate of MAPK de-phosphorylation, when the C-terminal end of MKP-3 was fused to the green fluorescent protein (GFP). Importantly, the fusion of GFP to MKP-3 did not alter the specificity of the phosphatase towards its MAPK substrates. We further show that conditional expression of MKP-3-GFP in this fibroblast cell line results in the inhibition of: (a) the phosphorylation of the p42/p44 MAPK substrates Elk1 and HIF-1,, (b) vascular endothelial growth factor (VEGF), cyclin D1, and c-fos gene transcription in response to MAPK pathway activation, and (c) cell proliferation. Finally, the MKP-3-GFP inducible cell line was transformed by Ha-ras and injected into nude mice. Treatment of mice with the tetracycline analog doxycycline resulted in a large delay in tumor emergence and growth as compared to the untreated control group, indicating that MKP-3-GFP activity is maintained in vivo. Altogether, these results show that inducible expression of MKP-3-GFP constitutes a valuable tool to study the role of p42/p44 MAPKs in various cellular responses in both cultured cell and animal models, a tool that may also be used to block unwanted cell growth in pathological conditions. © 2004 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||