Doxycycline Attenuates Lipopolysaccharide-Induced Microvascular Endothelial Cell Derangements.

PubMed

Wiggins-Dohlvik, Katie; Stagg, Hayden W; Han, Min Suk; Alluri, Himakarnika; Oakley, Ryan P; Anasooya Shaji, Chinchusha; Davis, Matthew L; Tharakan, Binu

2016-06-01

Lipopolysaccharide (LPS) is known to induce vascular derangements. The pathophysiology involved therein is unknown, but matrix metalloproteinases (MMPs) may be an important mediator. We hypothesized that in vitro LPS provokes vascular permeability, damages endothelial structural proteins, and increases MMP activity; that in vivo LPS increases permeability and fluid requirements; and that the MMP inhibitor doxycycline mitigates such changes. Rat lung microvascular endothelial cells were divided into four groups: control, LPS, LPS plus doxycycline, and doxycycline. Permeability, structural proteins β-catenin and Filamentous-actin, and MMP-9 activity were examined. Sprauge Dawley rats were divided into sham, IV LPS, and IV LPS plus IV doxycycline groups. Mesenteric postcapillary venules were observed. Blood pressure was measured as animals were resuscitated and fluid requirements were compared. Statistical analysis was conducted using Student's t-test and ANOVA. In vitro LPS increased permeability, damaged adherens junctions, induced actin stress fiber formation, and increased MMP-9 enzyme activity. In vivo, IV LPS administration induced vascular permeability. During resuscitation, significantly more fluid was necessary to maintain normotension in the IV LPS group. Doxycycline mitigated all derangements observed. We conclude that LPS increases permeability, damages structural proteins, and increases MMP-9 activity in endothelial cells. Additionally, endotoxemia induces hyperpermeability and increases the amount of IV fluid required to maintain normotension in vivo. Doxycycline mitigates such changes both in vitro and in vivo. Our findings illuminate the possible role of matrix metalloproteinases in the pathophysiology of lipopolysaccharide-induced microvascular hyperpermeability and pave the way for better understanding and treatment of this process.

Subantimicrobial dose doxycycline effects on osteopenic bone loss: microbiologic results.

PubMed

Walker, Clay; Puumala, Susan; Golub, Lorne M; Stoner, Julie A; Reinhardt, Richard A; Lee, Hsi-Ming; Payne, Jeffrey B

2007-08-01

Based on microbiologic concerns, the safety of a 24-month regimen of subantimicrobial dose doxycycline (SDD; 20 mg twice a day) was evaluated in postmenopausal osteopenic women with periodontitis in a double-blind, placebo-controlled, randomized clinical trial. Subgingival samples were collected from two sites (probing depth > or = 5 mm) in each of 128 subjects at baseline, with the same sites resampled at the conclusion of the 2-year period. The samples were enumerated on selective and non-selective media and on doxycycline (4 microg/ml) medium. Up to five different colonial morphologies were subcultured from the doxycycline medium, identified to species, and susceptibilities determined to doxycycline and five other antibiotics. Data were analyzed for microbial differences in total colony forming units (CFU), periodontal and opportunistic pathogens, and changes in species and in susceptibilities of isolates recovered on doxycycline medium. There was no significant evidence that changes in total anaerobic counts over the treatment period (P = 0.96) differed between treatment groups. Likewise, periodontal pathogens, opportunistic pathogens, or normal flora did not differ descriptively between groups. Although there was a significant increase (P <0.001) in the total CFU recovered from the 4 microg/ml doxycycline plates at 24 months for SDD versus placebo, the percentage that was clinically resistant to doxycycline (minimal inhibitory concentration [MIC] > or = 16 microg/ml) decreased over the 24-month period in both groups and did not differ between the treatment groups (SDD: 79% to 76%; placebo: 83% to 70%; P = 0.2). There were no significant differences (P >0.28 for each) in the change in cross-resistance between the groups for doxycycline and the other five antibiotics. No antimicrobial effect on the subgingival flora was detected following treatment with SDD for 24 months, relative to baseline or to placebo. The increase in initial resistance (at 4 microg/ml) did

Effect of iron ion on doxycycline photocatalytic and Fenton-based autocatatalytic decomposition.

PubMed

Bolobajev, Juri; Trapido, Marina; Goi, Anna

2016-06-01

Doxycycline plays a key role in Fe(III)-to-Fe(II) redox cycling and therefore in controlling the overall reaction rate of the Fenton-based process (H2O2/Fe(III)). This highlights the autocatalytic profile of doxycycline degradation. Ferric iron reduction in the presence of doxycycline relied on doxycycline-to-Fe(III) complex formation with an ensuing reductive release of Fe(II). The lower ratio of OH-to-contaminant in an initial H2O2/Fe(III) oxidation step than in that of classical Fenton (H2O2/Fe(II)) decreased the doxycycline degradation rate. The quantum yield of doxycycline in direct UV-C photolysis was 3.1 × 10(-3) M E(-1). In spite of doxycycline-Fe(III) complexes could produce the adverse effect on the doxycycline degradation in the UV/Fe(III) system some acceleration of the rate was observed upon irradiation of the Fe(III)-hydroxy complex. Acidic reaction media (pH 3.0) and the molar ratio of DC/Fe(III) = 2/1 favored the complex formation. Doxycycline close degradation rates and complete mineralization achieved for 120 min (Table 1) with both UV/H2O2 and UV/H2O2/Fe(III) indicated the unsubstantial role of the reduction of Fe(III) to Fe(II) in UV/H2O2/Fe(III) system efficacy. Thus, factors such as doxycycline's ability to form complexes with ferric iron and the ability of complexes to participate in a reductive pathway should be considered at a technological level in process optimization, with chemistry based on iron ion catalysis to enhance the doxycycline oxidative pathway. Copyright © 2016 Elsevier Ltd. All rights reserved.

Systemic Prophylaxis with Doxycycline in Surgery of the Colon and Rectum

PubMed Central

Höjer, H.; Wetterfors, J.

1978-01-01

A prospective double-blind study on the effects of doxycycline as a prophylactic antimicrobial in elective colonic surgery is presented. One hundred-eighteen patients were evaluated. Fifty-eight were treated and 60 were controls. Two hundred milligrams, doxycycline or placebo (two capsules) were given orally four to six hours prior to surgery and 100 mg or placebo (one capsule) for five days postoperatively. Doxycycline levels in serum and tissues were determined and related to the MICvalues of the contaminants of the operative field. A significantly lower incidence of abdominal wound sepsis, intra-abdominal complications, and septicemia was recorded in the doxycycline group compared to the control group, 12.1 and 45% respectively. The prophylactic effect was most pronounced in patients with a negative wound culture upon closure. Macroscopical peritoneal contamination was associated with less severe consequencies in the doxycycline group. Infections in the perineal field, 3/15 vs 8/17, appeared alone in the doxycycline group, whereas they were combined with abdominal sepsis in 6/8 among the controls. Treatment also reduced the incidence of repeat laparotomy due to septic complications, 0 vs 8. Thus systemic per and postoperative prophylaxis with doxycycline significantly reduced both the incidence and the severity of postoperative sepsis in potentially contaminated elective colorectal surgery without any adverse reactions. PMID:646474

Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation?

PubMed

Cross, Ruby; Ling, Clare; Day, Nicholas P J; McGready, Rose; Paris, Daniel H

2016-01-01

Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines - class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood. A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found. The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children.

Doxycycline concentration over time after storage in a compounded veterinary preparation.

PubMed

Papich, Mark G; Davidson, Gigi S; Fortier, Lisa A

2013-06-15

To determine the concentration of doxycycline compounded from doxycycline hyclate tablets into liquid formulations for oral administration in veterinary species and stored for 28 days. Evaluation study. Doxycycline hyclate tablets (100 mg) crushed and mixed with a 50:50 mixture of syrup and suspension vehicles for oral administration to produce 3 batches each of 2 doxycycline formulations: 33.3 and 166.7 mg/mL. Formulations were stored, protected from light, at room temperature (22° to 26°C [71.6° to 78.8°F]) and at a controlled cold temperature (refrigerated 2° to 8°C [35.6° to 46.4°F]). Doxycycline was extracted from the formulations, and concentration was measured by high-pressure liquid chromatography on days 0 (date of preparation), 1, 4, 7, 14, 21, and 28. Concentrations were compared with those of a US Pharmacopeial Convention reference standard. Formulation quality at each point was also assessed through color change, formulation consistency, and suspension uniformity. On days 0, 1, 4, and 7, the concentration of each formulation was within 90% to 110% of the reference standard (range, 93% to 109%), which was deemed acceptable. However, doxycycline concentrations had decreased dramatically by day 14 and remained low for the duration of the study period. Doxycycline concentrations on days 14, 21, and 28 were all < 20% (range, 14% to 18%) of the reference standard, and the quality of the formulations decreased as well. No effect of storage temperatures on doxycycline concentration was identified. The concentration of doxycycline, compounded from commercial tablets in the vehicles evaluated to yield doses of 33.3 and 166.7 mg/mL, cannot be assured beyond 7 days.

The Inhibitory Effect of Doxycycline on Cisplatin-Sensitive and -Resistant Epithelial Ovarian Cancer

PubMed Central

Ma, Bei; Xu, Ming-juan

2014-01-01

Background Detecting a new effective and hypotoxic anticancer drug is an emerging new strategy for cancer chemotherapy. Doxycycline (DC) is a kind of antibiotics but also inhibits tumorigenesis. Methods MTT and cell invasion assay, flow cytometry, western-blot analysis and nude mice were used to investigate the effects and underlying mechanisms of doxycycline on epithelial ovarian cancer cells. Results Doxycycline inhibited the proliferation and invasion of SKOV3 and SKOV3/DDP; induced moderate apoptosis of SKOV3/DDP. CXCR4 expression at both mRNA and protein levels was downregulated in both cell lines when treated with doxycycline. Akt and ERK1/2 were involved in doxycycline effect on cell proliferation of SKOV3 but not of SKOV3/DDP. Akt and EKR1/2 phosphorylation were activated by SDF-1α, which was then inhibited by doxycycline in SKOV3. Pro-caspase-3 expression was significantly higher in SKOV3 than that in SKOV3/DDP which was upregulated when treated with doxycycline. In vivo, doxycycline inhibited peritoneal tumor xenograft and decreased malignant ascites. Conclusion Doxycycline not only has an inhibitory effect on ovarian cancer, but also can increase sensitivity to cisplatin. SDF-1α/CXCR4-regulated Akt and ERK 1/2 activations are probably involved in the antitumor effect of doxycycline on SKOV3 cells, while upregulation of pro-caspase-3 may be the main mechanism involved in SKOV3/DDP cells. PMID:24598933

A randomized, comparative study of dual therapy (doxycycline-rifampin) versus triple therapy (doxycycline-rifampin-levofloxacin) for treating acute/subacute brucellosis.

PubMed

Hasanain, Ahmad; Mahdy, Reem; Mohamed, Asmaa; Ali, Mostafa

2016-01-01

The aim of this study was to compare both the efficacy and safety profile of the WHO-recommended, dual therapy (doxycycline-rifampin) to a quinolone-based, triple therapy (doxycycline-rifampin-levofloxacin) for treating acute/subacute brucellosis. We studied 107 consecutive, naïve patients with acute/subacute brucellosis admitted to Assiut University Hospital. Patients were randomly allocated to receive the dual therapy of doxycycline-rifampin (group-A) or to receive the triple therapy of doxycycline-rifampin-levofloxacin (group-B). Acute/subacute brucellosis was diagnosed based on the presence of: (1) contact with animals or fresh animal products, (2) suggestive clinical manifestations of less than one-year duration, and (3) positive antibody titer (1:160) by standard tube agglutination test. There was no significant difference between the two groups regarding their demographic data. Fever was the most frequent manifestation (96.3%). Epigastric pain was the most frequent adverse effect of treatment (12.1%). Group-A patients had a significantly higher relapse rate compared to group-B patients (22.6% versus 9.3%, p-value=0.01). The rate of treatment adverse effects was higher among group-B patients, although not reaching statistical significance (20.4% versus 11.3%, p-value=0.059). Adding levofloxacin to the dual therapy for acute/subacute brucellosis (doxycycline-rifampin) may increase its efficacy in terms of lowering the relapse rate of the disease. Further, larger scale studies are needed before considering modifying the standard, dual therapy for brucellosis. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.

The PK/PD Interactions of Doxycycline against Mycoplasma gallisepticum

PubMed Central

Zhang, Nan; Gu, Xiaoyan; Ye, Xiaomei; Wu, Xun; Zhang, Bingxu; Zhang, Longfei; Shen, Xiangguang; Jiang, Hongxia; Ding, Huanzhong

2016-01-01

Mycoplasma gallisepticum is one of the most important pathogens that cause chronic respiratory disease in chicken. This study investigated the antibacterial activity of doxycycline against M. gallisepticum strain S6. In static time–killing studies with constant antibiotic concentrations [0–64 minimum inhibitory concentration (MIC)], M. gallisepticum colonies were quantified and kill rates were calculated to estimate the drug effect. The half-life of doxycycline in chicken was 6.51 ± 0.63 h. An in vitro dynamic model (the drug concentrations are fluctuant) was also established and two half-lives of 6.51 and 12 h were simulated. The samples were collected for drug concentration determination and viable counting of M. gallisepticum. In static time–killing studies, doxycycline produced a maximum antimycoplasmal effect of 5.62log10 (CFU/mL) reduction and the maximum kill rate was 0.11 h−1. In the in vitro dynamic model, doxycycline had a mycoplasmacidal activity in the two regimens, and the maximum antimycoplasmal effects were 4.1 and 4.75log10 (CFU/mL) reduction, respectively. Furthermore, the cumulative percentage of time over a 48-h period that the drug concentration exceeds the MIC (%T > MIC) was the pharmacokinetic–pharmacodynamic index that best correlated with antimicrobial efficacy (R2 = 0.986, compared with 0.897 for the peak level divided by the MIC and 0.953 for the area under the concentration–time curve over 48 h divided by the MIC). The estimated %T > MIC values for 0log10 (CFU/mL) reduction, 2log10 (CFU/mL) reduction and 3log10 (CFU/mL) reduction were 32.48, 45.68, and 54.36%, respectively, during 48 h treatment period of doxycycline. In conclusion, doxycycline shows excellent effectiveness and time-dependent characteristics against M. gallisepticum strain S6 in vitro. Additionally, these results will guide optimal dosing strategies of doxycycline in M. gallisepticum infection. PMID:27199972

Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

PubMed Central

Wojciechowski, Jessica; Mudge, Stuart; Upton, Richard N.; Foster, David J. R.

2017-01-01

ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens. PMID:28052851

Doxycycline alters collagen composition following ventral hernia repair.

PubMed

Tharappel, Job C; Harris, Jennifer W; Totten, Crystal; Zwischenberger, Brittany A; Roth, John S

2017-04-01

Doxycycline, a nonspecific metalloproteinase (MMP) inhibitor, has been demonstrated to impact the strength of the polypropylene (PP) mesh-repaired hernia with an increase in the deposition of collagen type 1. The impact of doxycycline with porcine acellular dermal matrices (PADM) is unknown; therefore, we evaluated the impact of doxycycline administration upon hernia repair with PP and PADM mesh. Sprague-Dawley rats weighing ~400 g underwent laparotomy with creation of a midline ventral hernia. After a 27-day recovery, animals were randomly assigned to four groups of eight and underwent intraperitoneal underlay hernia repair with either PP or PADM. Groups were assigned to daily normal saline (S) or daily doxycycline in normal saline 10 mg/kg (D) via oral gavage for 8 weeks beginning 24 h preoperatively. Animals were euthanized at 8 weeks and underwent tensiometric testing of the abdominal wall and western blot analyses for collagen subtypes and MMPs. Thirty-two animals underwent successful hernia creation and repair with either PADM or PP. At 8 weeks, 15 of 16 PP-implanted animals survived with only 12 of 16 PADM-implanted animals surviving. There were no differences in the mesh to fascial interface tensiometric strength between groups. Densitometric counts in the PADM-D group demonstrated increased collagen type 1 compared to PP-S (PADM-D [1286.5], PADM-S [906.9], PP-S [700.4], p = 0.037) and decreased collagen type 3 compared to PP-S (PADM-D [7446.9], PADM-S [8507.6], PP-S [11,297.1], p = 0.01). MMP-9 levels were increased in PADM-D (PP-S vs. PADM-D, p = 0.04), while MMP-2 levels were similar between PADM-D and PADM-S, respectively. Collagen type 1 deposition at the mesh to fascial interface is enhanced following administration of doxycycline in ventral hernia repairs with porcine acellular dermal matrices. Doxycycline administration may have implications for enhancing hernia repair outcomes using biologic mesh.

Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach

PubMed Central

Nanda, Neha; Dhawan, Devinder K.; Bhatia, Alka; Mahmood, Akhtar; Mahmood, Safrun

2016-01-01

Background Doxycycline (DOX) exhibits anti-inflammatory, anti-tumor, and pro-apoptotic activity and is being tested in clinical trials as a chemotherapeutic agent for several cancers, including colon cancer. Materials & Methods In the current study, the chemotherapeutic activity of doxycycline was tested in a rat model of colon carcinogenesis, induced by colon specific cancer promoter, 1,2, dimethylhydrazine (DMH) as well as study the effect of DOX-alone on a separate group of rats. Results Doxycycline administration in DMH-treated rats (DMH-DOX) unexpectedly increased tumor multiplicity, stimulated progression of colonic tumor growth from adenomas to carcinomas and revealed metastasis in small intestine as determined by macroscopic and histopathological analysis. DOX-alone treatment showed markedly enhanced chronic inflammation and reactive hyperplasia, which was dependent upon the dose of doxycycline administered. Moreover, immunohistochemical analysis revealed evidence of inflammation and anti-apoptotic action of DOX by deregulation of various biomarkers. Conclusion These results suggest that doxycycline caused chronic inflammation in colon, small intestine injury, enhanced the efficacy of DMH in tumor progression and provided a mechanistic link between doxycycline-induced chronic inflammation and tumorigenesis. Ongoing studies thus may need to focus on the molecular mechanisms of doxycycline action, which lead to its inflammatory and tumorigenic effects. PMID:26998758

Revisiting doxycycline in pregnancy and early childhood – time to rebuild its reputation?

PubMed Central

Cross, Ruby; Ling, Clare; Day, Nicholas P. J.; McGready, Rose; Paris, Daniel H.

2016-01-01

ABSTRACT Introduction: Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines – class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood. Areas Covered: A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found. Expert Opinion: The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children. PMID:26680308

Doxycycline Inhibits Inflammation-Induced Lymphangiogenesis in Mouse Cornea by Multiple Mechanisms

PubMed Central

Huang, Jingwen; Zhou, Jingwen; Qiu, Sujuan; Liang, Dan

2014-01-01

Lymphangiogenesis is significantly involved in the pathogenesis of diseases, including graft rejection, cancer metastasis and various inflammatory conditions. The inhibition of lymphangiogenesis has become a new therapeutic target for the treatment of these diseases. Here, we explored the anti-lymphangiogenic effects of doxycycline in inflammation-induced lymphangiogenesis (ILA) in the cornea and the underlying mechanisms. In the present study, mice with ILA of the cornea were treated with topical doxycycline (0.1%) or vehicle control. Lymphangiogenesis was quantified using corneal immunostaining of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). Human dermal lymphatic endothelial cells (HDLECs) and a murine macrophage cell line (RAW264.7) were used to further explore the underlying mechanisms of doxycycline-mediated anti-lymphangiogenesis in vitro. Our results showed that doxycycline treatment dramatically inhibited ILA in the mouse cornea (p<0.001), with a significant decrease in vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 signalling, macrophage infiltration and inflammatory cytokine expression. Doxycycline also significantly inhibited VEGF-C-induced HDLEC proliferation in vitro by modulating the PI3K/Akt/endothelial nitric oxide (NO) synthase (eNOS) pathway and significantly suppressed interleukin-1β (IL-1β), TNF-α and VEGF-C production in the RAW264.7 cell line by modulating the PI3K/Akt/nuclear factor-kappaB (NF-κB) pathway. Additionally, doxycycline treatment dramatically reduced the phosphorylation of NF-κBp65, Akt and eNOS in ILA and significantly inhibited matrix metalloproteinases (MMPs) activity in vitro and in ILA. In conclusion, doxycycline inhibited ILA, possibly through suppression of VEGF-C signalling, macrophage function and MMPs activity. This observation suggests that doxycycline is a potential therapeutic agent for lymphangiogenesis-related diseases. PMID:25268699

Bioavailability of Tetracycline and Doxycycline in Fasted and Nonfasted Subjects

PubMed Central

Welling, Peter G.; Koch, Patricia A.; Lau, Curtis C.; Craig, William A.

1977-01-01

The influence of various test meals and fluid volumes on the relative bioavailability of commercial formulations of doxycycline hyclate and tetracycline hydrochloride was studied in healthy human volunteers. Serum levels of tetracycline were uniformly reduced by approximately 50% by all test meals, whereas serum levels of doxycycline were reduced by 20%. The reduction of tetracycline serum levels will likely be of clinical significance. The bioavailability of each drug was almost identical from an oral solution and from capsules in fasted subjects. The rate of doxycycline absorption was reduced when capsules were administered with a small volume of water, but the overall efficiency of absorption of both drugs was essentially independent of co-administered fluid volume. The use of 8-h serum data provides a reliable estimate of drug bioavailability for tetracycline and, to a lesser extent, for doxycycline. PMID:856000

Comparison of doxycycline with azithromycin in treatment of pharyngeal chlamydia infection.

PubMed

Manavi, K; Hettiarachchi, N; Hodson, J

2016-12-01

Recent data suggest that azithromycin may not be as effective as doxycycline in eradication of genital chlamydial infection. The aim of this study was to compare the eradication rate of pharyngeal Chlamydia trachomatis infection after treatment with azithromycin 1 g stat with that of doxycycline 100 mg twice a day for seven days. A prospective open-label observational study was conducted on patients with pharyngeal Chlamydia trachomatis diagnosed at Whittall Street Clinic, University Hospitals Birmingham, Birmingham, UK, between July 2012 and July 2013. We confirmed eradication of pharyngeal Chlamydia trachomatis with a negative test of cure. We treated all our patients with azithromycin 1 g stat until February 2013. At that stage, we offered doxycycline to patients with pharyngeal Chlamydia trachomatis A total of 398 patients (52 men, 346 women) were diagnosed with pharyngeal Chlamydia trachomatis during the study period. Of the 172 patients included in the final analysis, 78 were treated with azithromycin and 64 with doxycycline. Treatment failure was identified among 8/78 (10%) patients treated with azithromycin and 1/64 (2%) treated with doxycycline (absolute difference: 8 percentage points, 95% CI: 0-17%, p = 0.041). In our study, doxycycline 100 mg twice a day for seven days was associated with less treatment failure of oropharyngeal chlamydia compared with azithromycin 1 g stat Future randomised studies should investigate whether patients with pharyngeal Chlamydia trachomatis should be followed up with a test of cure when treated with azithromycin, or be treated with doxycycline. © The Author(s) 2016.

Doxycycline Sclerotherapy Is Superior in the Treatment of Pediatric Lymphatic Malformations.

PubMed

Thomas, Debi M; Wieck, Minna M; Grant, Christa N; Dossa, Avafia; Nowicki, Donna; Stanley, Phillip; Zeinati, Chadi; Howell, Lori K; Anselmo, Dean M

2016-12-01

To evaluate efficacy of sclerotherapy with doxycycline versus sodium tetradecyl sulfate (STS) for treatment of macrocystic and mixed lymphatic malformations (LMs). This single-center retrospective review identified 41 children (17 boys; 24 girls; age range, 1 month to 15.4 y) who underwent sclerotherapy with doxycycline (n = 32) or STS (n = 9) for macrocystic (n = 31) or mixed (n = 10) LMs. There were 114 treatments performed, averaging 2.8 treatments (range, 1-8 treatments) per patient. Average follow-up time was 10 months (range, 1-59 months). Clinical response was deemed excellent or moderate if > 90% or > 50% of LMs resolved based on visual estimate. With doxycycline, 87% of patients (28 of 32) had excellent or moderate response with an average of 2.8 treatments (range, 1-7 treatments); 13% required subsequent resection. With 3% STS monotherapy, only 55% of patients (5 of 9) had excellent or moderate response with an average of 2.8 treatments (range, 1-8 treatments), and 33% required subsequent resection. Significantly fewer patients treated with STS responded well compared with patients treated with doxycycline (P = .03). Patients treated with STS had significantly longer follow-up than patients treated with doxycycline (27 months vs 6 months, P = .0001). Doxycycline monotherapy resulted in a high rate of excellent clinical outcomes after a few treatments without increased need for subsequent operative resection. These results support use of doxycycline sclerotherapy as primary treatment for macrocystic and mixed LMs in children. Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.

Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data.

PubMed

Hopkins, Ashley M; Wojciechowski, Jessica; Abuhelwa, Ahmad Y; Mudge, Stuart; Upton, Richard N; Foster, David J R

2017-03-01

The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion ( P < 0.01) and then backward deletion ( P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability ( F ), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens. Copyright © 2017 American Society for Microbiology.

Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress

PubMed Central

Singh, Laishram Pradeepkumar; Mishra, Amartya; Saha, Debjit; Swarnakar, Snehasikta

2011-01-01

AIM: To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric injury. METHODS: Gastric ulcers were generated in rats by administration of 70% ethanol, and activity of doxycycline was tested by administration 30 min prior to ethanol. Similarly, the effect of doxycycline was tested in an indomethacin-induced gastric ulcer model. The activities and expression of MMPs were examined by zymography and Western blot analysis. RESULTS: Gastric injury in rats as judged by elevated ulcer indices following exposure to ulcerogen, either indomethacin or ethanol, was reversed significantly by doxycycline. Indomethacin-induced ulcerated gastric tissues exhibited about 12-fold higher proMMP-9 activity and about 5-fold higher proMMP-3 activity as compared to control tissues. Similarly, ethanol induced about 22-fold and about 6-fold higher proMMP-9 and proMMP-3 activities, respectively, in rat gastric tissues. Both proMMP-9 and MMP-3 activities were markedly decreased by doxycycline in ulcerogen treated rat gastric tissues. In contrast, the reduced MMP-2 activity in ulcerated tissues was increased by doxycycline during ulcer prevention. On the other hand, doxycycline inhibited significantly proMMP-9, -2 and -3 activities in vitro. In addition, doxycycline reduced oxidative load in gastric tissues and scavenged H2O2 in vitro. Our results suggest a novel regulatory role of doxycycline on MMP-2 activity in addition to inhibitory action on MMP-9 and MMP-3 during prevention of gastric ulcers. CONCLUSION: This is the first demonstration of dual action of doxycycline, that is, regulation of MMP activity and reduction of oxidative stress in arresting gastric injury. PMID:21876619

Doxycycline in Eradication Therapy of Helicobacter pylori--a Systematic Review and Meta-Analysis.

PubMed

Niv, Yaron

2016-01-01

Since resistance of Helicobacter pylori is developing very fast all over the world, new treatment regimens for eradication are urgently needed. To compare eradication success rate of H. pylori treatment regimens with and without doxycycline. English medical literature searches were conducted for regimens including doxycycline for eradication of H. pylori. Searches were performed up to August 31, 2015, using MEDLINE, PubMed, EMBASE, Scopus and CENTRAL. Meta-analysis was performed by using comprehensive meta-analysis software. Pooled ORs and 95% CIs were calculated comparing treatment regimens for eradication of H. pylori infection with and without doxycycline. The OR for eradication success rate in a fixed model was in favor for treatment regimens with doxycycline: 1.292, 95% CI 1.048-1.594, p = 0.016. There was no significant heterogeneity in the included studies: Q = 15.130, d.f. (Q) = 8, I2 = 47.126, p > 0.10. When treatment regimens with doxycycline were compared only with treatment regimens with tetracycline, no significant difference was found in eradication success rate: OR 0.95, 95% CI 0.68-1.32, p = 0.77. But when treatment regimens with doxycycline were compared with treatment regimens without tetracycline, the OR in favor of doxycycline was even higher: OR 1.59, 95% CI 1.21-2.09, p < 0.001. In this meta-analysis, we confirmed doxycycline efficiency in the eradication of H. pylori. Thus, triple, quadruple or even high dose dual therapy with regimens containing doxycycline should be considered. © 2016 S. Karger AG, Basel.

Comparison of Doxycycline and Benzathine Penicillin G for the Treatment of Early Syphilis.

PubMed

Xiao, Hailu; Liu, Dianchang; Li, Zhen; Zheng, Rongtao; Li, Zhongwei; Hou, Jianling; Zhang, Shengjia; Chu, Tongsheng; Tian, Hongqing; Zhang, Furen

2017-07-01

Doxycycline is the preferred recommended second-line treatment for the treatment of early syphilis. Recent reports showed a declining efficacy trend of doxycycline in treatment of early syphilis. The aim of our study was to assess the serological response to the treatment for early syphilis with doxycycline compared with benzathine penicillin G and evaluate whether doxycycline is still an effective agent for the treatment of early syphilis. A record-based retrospective study was conducted. Patients were diagnosed with early syphilis in an sexually transmitted disease (STD) clinic from January 1, 2008 to December 31, 2014. They were treated with a single dose of benzathine penicillin G 2.4MU or oral doxycycline 100 mg twice daily for 14 days. Pearson's chi-squared test was used for data analysis. 601 cases were included in the final study sample: 105 (17.5%) patients received a 14-day course of doxycycline (doxycycline group), and 496 (82.5%) patients received single-dose benzathine penicillin G (BPG group). The serological responses at 6 months and 12 months after treatment were compared. No statistically significant differences were found between the two groups at 6 months (69.52% vs. 75.00%, P=0.245), and at 12 months (92.38% vs. 96.17%, P=0.115). Doxycycline is still an effective agent for the treatment of early syphilis.

Airway-Specific Inducible Transgene Expression Using Aerosolized Doxycycline

PubMed Central

Tata, Purushothama Rao; Pardo-Saganta, Ana; Prabhu, Mythili; Vinarsky, Vladimir; Law, Brandon M.; Fontaine, Benjamin A.; Tager, Andrew M.

2013-01-01

Tissue-specific transgene expression using tetracycline (tet)-regulated promoter/operator elements has been used to revolutionize our understanding of cellular and molecular processes. However, because most tet-regulated mouse strains use promoters of genes expressed in multiple tissues, to achieve exclusive expression in an organ of interest is often impossible. Indeed, in the extreme case, unwanted transgene expression in other organ systems causes lethality and precludes the study of the transgene in the actual organ of interest. Here, we describe a novel approach to activating tet-inducible transgene expression solely in the airway by administering aerosolized doxycycline. By optimizing the dose and duration of aerosolized doxycycline exposure in mice possessing a ubiquitously expressed Rosa26 promoter–driven reverse tet-controlled transcriptional activator (rtTA) element, we induce transgene expression exclusively in the airways. We detect no changes in the cellular composition or proliferative behavior of airway cells. We used this newly developed method to achieve airway basal stem cell–specific transgene expression using a cytokeratin 5 (also known as keratin 5)–driven rtTA driver line to induce Notch pathway activation. We observed a more robust mucous metaplasia phenotype than in mice receiving doxycycline systemically. In addition, unwanted phenotypes outside of the lung that were evident when doxycycline was received systemically were now absent. Thus, our approach allows for rapid and efficient airway-specific transgene expression. After the careful strain by strain titration of the dose and timing of doxycycline inhalation, a suite of preexisting transgenic mice can now be used to study airway biology specifically in cases where transient transgene expression is sufficient to induce a phenotype. PMID:23848320

Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection.

PubMed

Geisler, William M; Uniyal, Apurva; Lee, Jeannette Y; Lensing, Shelly Y; Johnson, Shacondra; Perry, Raymond C W; Kadrnka, Carmel M; Kerndt, Peter R

2015-12-24

Urogenital Chlamydia trachomatis infection remains prevalent and causes substantial reproductive morbidity. Recent studies have raised concern about the efficacy of azithromycin for the treatment of chlamydia infection. We conducted a randomized trial comparing oral azithromycin with doxycycline for the treatment of urogenital chlamydia infection among adolescents in youth correctional facilities, to evaluate the noninferiority of azithromycin (1 g in one dose) to doxycycline (100 mg twice daily for 7 days). The treatment was directly observed. The primary end point was treatment failure at 28 days after treatment initiation, with treatment failure determined on the basis of nucleic acid amplification testing, sexual history, and outer membrane protein A (OmpA) genotyping of C. trachomatis strains. Among the 567 participants enrolled, 284 were randomly assigned to receive azithromycin, and 283 were randomly assigned to receive doxycycline. A total of 155 participants in each treatment group (65% male) made up the per-protocol population. There were no treatment failures in the doxycycline group. In the azithromycin group, treatment failure occurred in 5 participants (3.2%; 95% confidence interval, 0.4 to 7.4%). The observed difference in failure rates between the treatment groups was 3.2 percentage points, with an upper boundary of the 90% confidence interval of 5.9 percentage points, which exceeded the prespecified absolute 5-percentage-point cutoff for establishing the noninferiority of azithromycin. In the context of a closed population receiving directly observed treatment for urogenital chlamydia infection, the efficacy of azithromycin was 97%, and the efficacy of doxycycline was 100%. The noninferiority of azithromycin was not established in this setting. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00980148.).

Considerations for using minocycline vs doxycycline for treatment of canine heartworm disease.

PubMed

Papich, Mark G

2017-11-09

Doxycycline has been considered the first drug of choice for treating Wolbachia, a member of the Rickettsiaceae, which has a symbiotic relationship with filarial worms, including heartworms. Wolbachia, is susceptible to tetracyclines, which have been used as adjunctive treatments for heartworm disease. Treatment with doxycycline reduces Wolbachia numbers in all stages of heartworms and improves outcomes and decreased microfilaremia in dogs treated for heartworm disease. The American Heartworm Society recommends treatment with doxycycline in dogs diagnosed with heartworm disease at a dose of 10 mg/kg twice daily for 28 days. If doxycycline is not available, minocycline can be considered as a substitute. However, minocycline has not undergone an evaluation in dogs with heartworm disease, nor has an effective dose been established. Minocycline is an attractive option because of the higher cost of doxycycline and new pharmacokinetic information for dogs that provides guidance for appropriate dosage regimens to achieve pharmacokinetic-pharmacodynamic (PK-PD) targets. Published reports from the Anti-Wolbachia Consortium (A-WOL) indicate superior in vitro activity of minocycline over doxycycline. Studies performed in mouse models to measure anti-Wolbachia activity showed that minocycline was 1.7 times more effective than doxycycline, despite a 3-fold lower pharmacokinetic exposure. To achieve the same exposure as achieved in the mouse infection model, a pharmacokinetic-pharmacodynamic (PK-PD) analysis was conducted to determine optimal dosages for dogs. The analysis showed that an oral minocycline dose of 3.75 to 5 mg/kg administered twice daily would attain similar targets as observed in mice and predicted for human infections. There are potentially several advantages for use of minocycline in animals. It is well absorbed from oral administration, it has less protein binding than doxycycline (65% vs 92%) allowing for better distribution into tissue, and it is

Doxycycline Indirectly Inhibits Proteolytic Activation of Tryptic Kallikrein-Related Peptidases and Activation of Cathelicidin

PubMed Central

Kanada, Kimberly N.; Nakatsuji, Teruaki; Gallo, Richard L.

2014-01-01

The increased abundance and activity of cathelicidin and kallikrein 5 (KLK5), a predominant trypsin-like serine protease (TLSP) in the stratum corneum, have been implicated in the pathogenesis of rosacea, a disorder treated by the use of low-dose doxycycline. Here we hypothesized that doxycycline can inhibit activation of tryptic KLKs through an indirect mechanism by inhibition of matrix metalloproteinases (MMPs) in keratinocytes. The capacity of doxycycline to directly inhibit enzyme activity was measured in surface collections of human facial skin and extracts of cultured keratinocytes by fluorescence polarization assay against fluorogenic substrates specific for MMPs or TLSPs. Doxycycline did inhibit MMP activity but did not directly inhibit serine protease activity against a fluorogenic substrate specific for TLSPs. However, when doxycycline or other MMP inhibitors were added to live keratinocytes during the production of tryptic KLKs, this treatment indirectly resulted in decreased TLSP activity. Furthermore, doxycycline under these conditions inhibited the generation of the cathelicidin peptide LL-37 from its precursor protein hCAP18, a process dependent on KLK activity. These results demonstrate that doxycycline can prevent cathelicidin activation, and suggest a previously unknown mechanism of action for doxycycline through inhibiting generation of active cathelicidin peptides. PMID:22336948

A new therapeutic association to manage relapsing experimental colitis: Doxycycline plus Saccharomyces boulardii.

PubMed

Garrido-Mesa, José; Algieri, Francesca; Rodriguez-Nogales, Alba; Utrilla, Maria Pilar; Rodriguez-Cabezas, Maria Elena; Zarzuelo, Antonio; Ocete, Maria Angeles; Garrido-Mesa, Natividad; Galvez, Julio

2015-07-01

Immunomodulatory antibiotics have been proposed for the treatment of multifactorial conditions such as inflammatory bowel disease. Probiotics are able to attenuate intestinal inflammation, being considered as safe when chronically administered. The aim of the study was to evaluate the anti-inflammatory effects of doxycycline, a tetracycline with immunomodulatory properties, alone and in association with the probiotic Saccharomyces boulardii CNCMI-745. Doxycycline was assayed both in vitro (Caco-2 epithelial cells and RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis and the dextran sodium sulfate (DSS) model of mouse colitis. In addition, the anti-inflammatory effect of the association of doxycycline and the probiotic was evaluated in vitro and in vivo in a DSS model of reactivated colitis in mice. Doxycycline displayed immunomodulatory activity in vitro, reducing IL-8 production by intestinal epithelial cells and nitric oxide by macrophages. Doxycycline administration to TNBS-colitic rats (5, 10 and 25 mg/kg) ameliorated the intestinal inflammatory process, being its efficacy comparable to that previously showed by minocycline. Doxycycline treatment was also effective in reducing acute intestinal inflammation in the DSS model of mouse colitis. The association of doxycycline and S. boulardii helped managing colitis in a reactivated model of colitis, by reducing intestinal inflammation and accelerating the recovery and attenuating the relapse. This was evidenced by a reduced disease activity index, colonic tissue damage and expression of inflammatory mediators. This study confirms the intestinal anti-inflammatory activity of doxycycline and supports the potential use of its therapeutic association with S. boulardii for the treatment of inflammatory bowel diseases, in which doxycycline is used to induce remission and long term probiotic administration helps to prevent the relapses. Copyright © 2015 Elsevier Ltd. All

Doxycycline Enhances Survival and Self-Renewal of Human Pluripotent Stem Cells

PubMed Central

Chang, Mi-Yoon; Rhee, Yong-Hee; Yi, Sang-Hoon; Lee, Su-Jae; Kim, Rae-Kwon; Kim, Hyongbum; Park, Chang-Hwan; Lee, Sang-Hun

2014-01-01

Summary We here report that doxycycline, an antibacterial agent, exerts dramatic effects on human embryonic stem and induced pluripotent stem cells (hESC/iPSCs) survival and self-renewal. The survival-promoting effect was also manifest in cultures of neural stem cells (NSCs) derived from hESC/iPSCs. These doxycycline effects are not associated with its antibacterial action, but mediated by direct activation of a PI3K-AKT intracellular signal. These findings indicate doxycycline as a useful supplement for stem cell cultures, facilitating their growth and maintenance. PMID:25254347

Doxycycline delivery from PLGA microspheres prepared by a modified solvent removal method.

PubMed

Patel, Roshni S; Cho, Daniel Y; Tian, Cheng; Chang, Amy; Estrellas, Kenneth M; Lavin, Danya; Furtado, Stacia; Mathiowitz, Edith

2012-01-01

We report on the development of a modified solvent removal method for the encapsulation of hydrophilic drugs within poly(lactic-co-glycolic acid) (PLGA). Using a water/oil/oil double emulsion, hydrophilic doxycycline was encapsulated within PLGA spheres with particle diameters ranging from approximately 600 nm to 19 µm. Encapsulation efficiencies of up to 74% were achieved for theoretical loadings from 1% to 10% (w/w), with biphasic release over 85 days with nearly complete release at the end of this time course. About 1% salt was added to the formulations to examine its effects on doxycycline release; salt modulated release only by increasing the magnitude of initial release without altering kinetics. Fourier transform infrared spectroscopy indicated no characteristic differences between doxycycline-loaded and control spheres. Differential scanning calorimetry and X-ray diffraction suggest that there may be a molecular dispersion of the doxycycline within the spheres and the doxycycline may be in an amorphous state, which could explain the slow, prolonged release of the drug.

Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells.

PubMed

Qin, Yuan; Zhang, Qiang; Lee, Shan; Zhong, Wei-Long; Liu, Yan-Rong; Liu, Hui-Juan; Zhao, Dong; Chen, Shuang; Xiao, Ting; Meng, Jing; Jing, Xue-Shuang; Wang, Jing; Sun, Bo; Dai, Ting-Ting; Yang, Cheng; Sun, Tao; Zhou, Hong-Gang

2015-12-01

The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.

Lack of Doxycycline Antimalarial Prophylaxis Impact on Staphylococcus aureus Tetracycline Resistance

PubMed Central

Mende, Katrin; Beckius, Miriam L.; Zera, Wendy C.; Yu, Xin; Li, Ping; Tribble, David R.; Murray, Clinton K.

2016-01-01

There is concern that susceptibility of Staphylococcus aureus to tetracyclines may decrease due to use of antimalarial prophylaxis (doxycycline). We examined characteristics related to tetracycline resistance, including doxycycline exposure, in S. aureus isolates collected via admission surveillance swabs and inpatient clinical cultures from United States military personnel injured during deployment (June 2009-January 2012). Tetracycline class resistance was determined using antimicrobial susceptibility testing. The first S. aureus isolate from 168 patients were analyzed, of which 38 (23%) isolates were resistant to tetracyclines (class). Tetracycline-resistant isolates had a higher proportion of resistance to clindamycin (p=0.019) compared to susceptible isolates. There was no significant difference in tetracycline resistance between isolates collected from patients with and without antimalarial prophylaxis; however, significantly more isolates had tet(M) resistance genes in the doxycycline exposure group (p=0.031). Despite 55% of the patients receiving doxycycline as antimalarial prophylaxis, there was no association with resistance to tetracyclines. PMID:27460426

Simple colorimetric detection of doxycycline and oxytetracycline using unmodified gold nanoparticles

NASA Astrophysics Data System (ADS)

Li, Jie; Fan, Shumin; Li, Zhigang; Xie, Yuanzhe; Wang, Rui; Ge, Baoyu; Wu, Jing; Wang, Ruiyong

2014-08-01

The interaction between tetracycline antibiotics and gold nanoparticles was studied. With citrate-coated gold nanoparticles as colorimetric probe, a simple and rapid detection method for doxycycline and oxytetracycline has been developed. This method relies on the distance-dependent optical properties of gold nanoparticles. In weakly acidic buffer medium, doxycycline and oxytetracycline could rapidly induce the aggregation of gold nanoparticles, resulting in red-to-blue (or purple) colour change. The experimental parameters were optimized with regard to pH, the concentration of the gold nanoparticles and the reaction time. Under optimal experimental conditions, the linear range of the colorimetric sensor for doxycycline/oxytetracycline was 0.06-0.66 and 0.59-8.85 μg mL-1, respectively. The corresponding limit of detection for doxycycline and oxytetracycline was 0.0086 and 0.0838 μg mL-1, respectively. This assay was sensitive, selective, simple and readily used to detect tetracycline antibiotics in food products.

Methicillin-susceptible, Doxycycline-resistant Staphylococcus aureus, Côte d’Ivoire

PubMed Central

Haus-Cheymol, Rachel; Dubrous, Philippe; Verret, Catherine; Spiegel, André; Bonnet, Richard; Bes, Michèle; Laurichesse, Henri; Beytout, Jean; Etienne, Jerome; Migliani, René; Koeck, Jean Louis

2007-01-01

We report 2 outbreaks of Panton-Valentine leukocidin–positive, doxycycline-resistant, methicillin-susceptible Staphylococcus aureus infections in French soldiers operating in Côte d’Ivoire. In a transssectional survey, nasal carriage of this strain was found in 2.9% of 273 soldiers about to be sent to Côte d’Ivoire and was associated with prior malaria prophylaxis with doxycycline. PMID:17552109

75 FR 61489 - Renewal of Declaration Regarding Emergency Use of Doxycycline Hyclate Tablets Accompanied by...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-05

... Emergency Use of Doxycycline Hyclate Tablets Accompanied by Emergency Use Information AGENCY: Office of the... the authorization of emergency use of doxycycline hyclate tablets accompanied by emergency use... authorization of the emergency use of doxycycline hyclate tablets accompanied by emergency use information...

Minocycline and Doxycycline, but not Tetracycline, Mitigate Liver and Kidney Injury after Hemorrhagic Shock/Resuscitation*

PubMed Central

Kholmukhamedov, Andaleb; Czerny, Christoph; Hu, Jiangting; Schwartz, Justin; Zhong, Zhi; Lemasters, John J.

2014-01-01

Background Despite recovery of hemodynamics by fluid resuscitation after hemorrhage, development of the systemic inflammatory response and multiple organ dysfunction syndromes can nonetheless lead to death. Minocycline and doxycycline are tetracycline derivatives that are protective in models of hypoxic, ischemic and oxidative stress. Our Aim was to determine whether minocycline and doxycycline protect liver and kidney and improve survival in a mouse model of hemorrhagic shock and resuscitation. Methods Mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood followed by half the shed volume of lactated Ringer's solution containing tetracycline (10 mg/kg), minocycline (10 mg/kg), doxycycline (5 mg/kg) or vehicle. For pre-plus post-treatment, drugs were administered intraperitoneally prior to hemorrhage followed by second equal dose in Ringer's solution after blood resuscitation. Blood and tissue were harvested after 6 h. Results Serum alanine aminotransferase (ALT) increased to 1988 and 1878 U/L after post-treatment with vehicle and tetracycline, respectively, whereas minocycline and doxycycline post-treatment decreased ALT to 857 and 863 U/L. Pre-plus post-treatment with minocycline and doxycycline also decreased ALT to 849 and 834 U/L. After vehicle, blood creatinine increased to 279 μM, which minocycline and doxycycline post-treatment decreased to 118 and 112 μM. Minocycline and doxycycline pre- plus post-treatment decreased creatinine similarly. Minocycline and doxycycline also decreased necrosis and apoptosis in liver and apoptosis in both liver and kidney, the latter assessed by TUNEL and caspase-3 activation. Lastly after 4.5 h of hemorrhage followed by resuscitation, minocycline and doxycycline (but not tetracycline) post-treatment improved 1-week survival from 38%(vehicle) to 69% and 67%, respectively. Conclusion Minocycline and doxycycline were similarly protective when given before as after blood resuscitation and might therefore

Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration.

PubMed

Yang, F; Si, H B; Wang, Y Q; Zhao, Z S; Zhou, B H; Hao, X Q

2016-08-01

The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (Vd) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (β) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (Ka), peak concentration (Cmax), time to reach Cmax (tmax) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 μg/ml, 1.73 ± 0.75 h and 52.33%, respectively. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells

PubMed Central

Liu, Yan-rong; Liu, Hui-juan; Zhao, Dong; Chen, Shuang; Xiao, Ting; Meng, Jing; Jing, Xue-shuang; Wang, Jing; Sun, Bo; Dai, Ting-ting; Yang, Cheng; Sun, Tao; Zhou, Hong-gang

2015-01-01

The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients. PMID:26512779

Formation of β-Cyclodextrin inclusion compound with doxycycline: A theoretical approach

NASA Astrophysics Data System (ADS)

Peraro, Cristian R.; Anconi, Amanda C. S. A.; Anconi, Cleber P. A.

2018-01-01

Recently, the inclusion compound formed by doxycycline and modified CD was investigated. In the inclusion compound, the unstable site of doxycycline was protected by the hydrophobic CD cavity. However, the guest arrangement inside CD cavity has not identified. In some situations, the correlation between protons of the guest and host in a 2D-ROESY experiment can be compatible with head and tail spatial arrangements. In the present work, the most stable guest spatial arrangement for the inclusion of doxycycline into β-CD was evaluated at B97-D/6-311++(2d,p) level of theory. For sake of comparison, tetracycline inclusion compound was also studied.

Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase

PubMed Central

WANG, CHUNHUAI; XIANG, RU; ZHANG, XIANGZHONG; CHEN, YUNXIAN

2015-01-01

Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix-coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti-β1-integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, incubation with blocking anti-β1-integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia. PMID:26004127

Doxycycline Stabilizes Vulnerable Plaque via Inhibiting Matrix Metalloproteinases and Attenuating Inflammation in Rabbits

PubMed Central

Dong, Mei; Zhong, Lin; Chen, Wen Qiang; Ji, Xiao Ping; Zhang, Mei; Zhao, Yu Xia; Li, Li; Yao, Gui Hua; Zhang, Peng Fei; Zhang, Cheng; Zhang, Lei; Zhang, Yun

2012-01-01

Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels. PMID:22737253

Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs.

PubMed

Ruiz, Sara Melisa Arciniegas; Olvera, Lilia Gutiérrez; Chacón, Sara del Carmen Caballero; Estrada, Dinorah Vargas

2015-04-01

To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy

PubMed Central

Tan, Qian; Yan, Xiaoqiong; Song, Lin; Yi, Hongxiang; Li, Ping; Sun, Guobin; Yu, Danfang; Li, Le; Zeng, Zheng; Guo, Zhenli

2017-01-01

Background Inducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment. Material/Methods The effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice. Results Doxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti-proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress. Conclusions In our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma. PMID:28842551

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy.

PubMed

Tan, Qian; Yan, Xiaoqiong; Song, Lin; Yi, Hongxiang; Li, Ping; Sun, Guobin; Yu, Danfang; Li, Le; Zeng, Zheng; Guo, Zhenlin

2017-08-26

BACKGROUND Inducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment. MATERIAL AND METHODS The effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice. RESULTS Doxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti-proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress. CONCLUSIONS In our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma.

Effects of matrix metalloproteinase inhibitor doxycycline and CD147 antagonist peptide-9 on gallbladder carcinoma cell lines.

PubMed

Wang, Shihang; Liu, Chao; Liu, Xinjiang; He, Yanxin; Shen, Dongfang; Luo, Qiankun; Dong, Yuxi; Dong, Haifeng; Pang, Zhigang

2017-10-01

Gallbladder carcinoma is the most common and aggressive malignancy of the biliary tree and highly expresses CD147, which is closely related to disease prognosis in a variety of human cancers. Doxycycline exhibited anti-tumor properties in many cancer cells. CD147 antagonist peptide-9 is a polypeptide and can specifically bind to CD147. The effect of these two drugs on gallbladder cancer cells has not been studied. The aim of this study is to investigate the effect of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells and the possible mechanism of inhibition on cancer cell of doxycycline. To investigate the effects of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells (GBC-SD and SGC-996), cell proliferation, CD147 expression, and early-stage apoptosis rate were measured after treated with doxycycline. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were measured after treated with different concentrations of doxycycline, antagonist peptide-9, and their combination. The results demonstrated that doxycycline inhibited cell proliferation, reduced CD147 expression level, and induced an early-stage apoptosis response in GBC-SD and SGC-996 cells. The matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were inhibited by antagonist peptide-9 and doxycycline, and the inhibitory effects were enhanced by combined drugs in gallbladder carcinoma cell lines. Taken together, doxycycline showed inhibitory effects on gallbladder carcinoma cell lines and reduced the expression of CD147, and this may be the mechanism by which doxycycline inhibits cancer cells. This study provides new information and tries to implement the design of adjuvant therapy method for gallbladder carcinoma.

Potent Synergistic Effect of Doxycycline with Fluconazole against Candida albicans Is Mediated by Interference with Iron Homeostasis

PubMed Central

2012-01-01

Doxycycline was found to act synergistically with the antifungal fluconazole against Candida albicans. Combination with doxycycline converts fluconazole from fungistatic to fungicidal, prevents the onset of drug resistance, and is also effective against a clinical isolate characterized by elevated resistance to fluconazole. Investigation of the interactions between the two drugs by way of checkerboard assays indicated that doxycycline had an influence on the MIC for fluconazole, as defined by CLSI standards, only at high concentrations (200 μg/ml). However, lower concentrations were effective at eliminating residual cell growth at supra-MICs of fluconazole. Using MIC-0, defined as a drug combination resulting in optically clear wells, as an endpoint, doxycycline was found to be synergistic with fluconazole at a concentration as low as 25 μg/ml, with a fractional inhibitory concentration index of <0.5. Doxycycline-mediated growth inhibition can be reversed by externally added iron, indicating that iron depletion may account for the synergism. Consistently, we confirmed old literature data about iron-chelating activity of doxycycline. Synergism of fluconazole with doxycycline does not appear to be mediated by calcineurin, since doxycycline further aggravates the susceptibility to fluconazole of mutants lacking the catalytic or the regulatory subunits of calcineurin. Growth in the presence of fluconazole and doxycycline is restored by an elevated dosage of ERG11 in Saccharomyces cerevisiae but not in C. albicans, despite the full competence of the pathogen's protein to act as a suppressor in baker's yeast. PMID:22564841

Doxycycline Suppresses Microglial Activation by Inhibiting the p38 MAPK and NF-kB Signaling Pathways.

PubMed

Santa-Cecília, Flávia V; Socias, Benjamin; Ouidja, Mohand O; Sepulveda-Diaz, Julia E; Acuña, Leonardo; Silva, Rangel L; Michel, Patrick P; Del-Bel, Elaine; Cunha, Thiago M; Raisman-Vozari, Rita

2016-05-01

In neurodegenerative diseases, the inflammatory response is mediated by activated glial cells, mainly microglia, which are the resident immune cells of the central nervous system. Activated microglial cells release proinflammatory mediators and neurotoxic factors that are suspected to cause or exacerbate these diseases. We recently demonstrated that doxycycline protects substantia nigra dopaminergic neurons in an animal model of Parkinson's disease. This effect was associated with a reduction of microglial cell activation, which suggests that doxycycline may operate primarily as an anti-inflammatory drug. In the present study, we assessed the anti-inflammatory potential of doxycycline using lipopolysaccharide (LPS)-activated primary microglial cells in culture as a model of neuroinflammation. Doxycycline attenuated the expression of key activation markers in LPS-treated microglial cultures in a concentration-dependent manner. More specifically, doxycycline treatment lowered the expression of the microglial activation marker IBA-1 as well as the production of ROS, NO, and proinflammatory cytokines (TNF-α and IL-1β). In primary microglial cells, we also found that doxycycline inhibits LPS-induced p38 MAP kinase phosphorylation and NF-kB nuclear translocation. The present results indicate that the effect of doxycycline on LPS-induced microglial activation probably occurs via the modulation of p38 MAP kinase and NF-kB signaling pathways. These results support the idea that doxycycline may be useful in preventing or slowing the progression of PD and other neurodegenerative diseases that exhibit altered glia function.

Seven days of doxycycline is an effective treatment for asymptomatic rectal Chlamydia trachomatis infection.

PubMed

Elgalib, A; Alexander, S; Tong, C Y W; White, J A

2011-08-01

There are no evidence-based guidelines for the specific management of rectal Chlamydia trachomatis (CT) infection. All men who have sex with men (MSM) diagnosed with asymptomatic rectal CT by nucleic acid amplification test (NAAT) at a large London genitourinary (GU) medicine clinic between September 2006 and September 2009 were offered oral doxycycline 100 mg twice daily for seven days and invited for a test of cure (TOC) by CT NAAT four weeks after treatment. A total of 487 asymptomatic rectal CT infections were diagnosed and analysis was restricted to 165 TOCs from men whose only treatment had been doxycycline for seven days. The median time post-treatment for TOC was 45 days (interquartile range [IQR], 34-88). Only two patients tested CT-positive at follow-up. One had taken doxycycline only for three days; the other attended for TOC 240 days after the completion of doxycycline treatment and at this time presented with new symptoms in the context of ongoing high sexual risk. Our findings show that doxycycline 100 mg twice daily for seven days is highly effective treatment for asymptomatic rectal CT infection, achieving clearance of CT in 98.8% (163/165; 95% CI 95.4-99.9%) of cases. We advocate doxycycline for seven days as first-line therapy for asymptomatic rectal CT.

Doxycycline affects gene expression profiles in aortic tissues in a rat model of vascular calcification.

PubMed

Lu, Hailin; Jiang, Wenhong; Yang, Han; Qin, Zhong; Guo, Si-En; Hu, Ming; Qin, Xiao

2017-11-01

Vitamin D 3 -induced vascular calcification (VC) in rats shares many phenotypical similarities with calcification occurring in human atherosclerosis, diabetes mellitus and chronic kidney disease, thereby it is a reliable model for identifying chemopreventive agents. Doxycycline has been shown to effectively attenuated VC. This study aimed to explore the effects of doxycycline on gene expression profiles in VC rats. The model of VC in rats was established by subcutaneous injection of vitamin D3 for 3days. Doxycycline at 120mgkg -1 day -1 was given via subcutaneous injection for 14days. Rat pathological changes, calcium deposition and calcium content in aortic tissues were measured by Hematoxylin-eosin, von Kossa staining and colorimetry, respectively. The gene change profile of aortic tissues after doxycycline treatment was assessed by Gene Microarray analysis using the Agilent Whole Rat Genome Oligo Microarray. The results showed that doxycycline significantly decreased the deposition of calcium, reduced the relative calcification area and alleviated pathological injury in aortic tissues. In addition, doxycycline treatment altered 88 gene expressions compared with untreated VD group. Of these, 61 genes were down-regulated and 27 genes were up-regulated. The functions of differentially expressed (DE) genes were involved in neutrophil chemotaxis, chronic inflammatory response, negative regulation of apoptotic process, cellular response to mechanical stimulus and immune response, etc. In conclusions, this study might provide the potential novel insights into the molecular mechanisms of doxycycline on VC. Copyright © 2017. Published by Elsevier Inc.

Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. The GECMEI Group. Grupo de Estudio de Castilla-la Mancha de Enfermedades Infecciosas.

PubMed

Solera, J; Rodríguez-Zapata, M; Geijo, P; Largo, J; Paulino, J; Sáez, L; Martínez-Alfaro, E; Sánchez, L; Sepulveda, M A; Ruiz-Ribó, M D

1995-09-01

Brucellosis is a common zoonosis in many parts of the world; the best regimen for the treatment of brucellosis has not been clearly determined. We have carried out a multicenter, open, controlled trial in five general hospitals in Spain to compare the efficacy and safety of doxycycline and rifampin (DR) versus doxycycline and streptomycin (DS) for the treatment of human brucellosis. The study included 194 ambulatory or hospitalized patients with acute brucellosis, without endocarditis or neurobrucellosis. The diagnostic criterion was isolation of Brucella species from blood or other tissues (n = 120) or a standard tube agglutination titer of 1/160 or more for anti-Brucella antibodies with compatible clinical findings (n = 74). Patients were randomly assigned to receive either 100 mg of doxycycline twice daily plus rifampin, 900 mg/day, in a single morning dose for 45 days (DR group) or the same dose of doxycycline for 45 days plus streptomycin, 1 g/day, intramuscularly for 14 days (DS group). A lack of therapeutic efficacy developed in 8 of the 100 patients in the DR group (8%) and in 2 of the 94 patients in the DS group (2%)(P = 0.10). Relapses occurred in 16 of the 100 patients in the DR group (16%) but in only 5 of the 94 patients in the DS group (5.3%) (P = 0.02). When relapse was considered in combination with initial lack of efficacy, 26 patients in the DR group (24%) and 7 patients in the DS group (7.45%) failed to respond to therapy (P = 0.0016). In general, therapy was well tolerated and only four patients (4%) in the DR group and two (2%) in the DS group had episodes of adverse effects necessitating discontinuation of treatment (P> 0.2). We conclude that a doxycycline-and-rifampin regimen is less effective than the doxycycline-and-streptomycin regimen in patients with acute brucellosis.

Doxycycline inhibits TGF-β1-induced extracellular matrix production in nasal polyp-derived fibroblasts.

PubMed

Shin, Jae-Min; Park, Joo-Hoo; Park, Il-Ho; Lee, Heung-Man

2016-03-01

Doxycycline has been shown to have antibacterial and anti-inflammatory effects and suppresses collagen biosynthesis. The purpose of this study was to evaluate the effects of doxycycline on transforming growth factor (TGF)-β1-induced myofibroblast differentiation and extracellular matrix production in nasal polyp-derived fibroblasts (NPDFs). We also determined the molecular mechanisms of action for doxycycline. NPDFs were isolated from nasal polyps from 8 patients. Doxycycline was used to pretreat TGF-β1-induced NPDFs. Cytotoxicity was evaluated using a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Expression levels of α-smooth muscle actin (SMA) and fibronectin were measured using Western blot, reverse-transcription polymerase chain reaction, and immunofluorescence staining. Total collagen production was analyzed with the Sircol collagen assay, while mitogen-activated protein kinase (MAPK) and NF-κB activation were determined using Western blot analysis. Luciferase assay was used to evaluate the transcriptional activity of NF-κB. Although doxycycline (0 to 40 μg/mL) had no significant cytotoxic effects in TGF-β1-induced NPDFs, it significantly reduced the expression levels of α-SMA, fibronectin, and collagen in TGF-β1-induced NPDFs in a dose-dependent manner. Doxycycline also inhibited the TGF-β1-induced activation of p38, c-Jun NH2 -terminal kinase (JNK), and NF-κB, and its inhibitory effects were similar to those of the specific inhibitors for each. Doxycycline has an inhibitory effect on TGF-β1-induced myofibroblast differentiation and extracellular matrix production via the p38 and JNK/NF-κB signal pathways in NPDFs. © 2015 ARS-AAOA, LLC.

Therapeutic effects of topical doxycycline in a benzalkonium chloride-induced mouse dry eye model.

PubMed

Zhang, Zhen; Yang, Wen-Zhao; Zhu, Zhen-Zhen; Hu, Qian-Qian; Chen, Yan-Feng; He, Hui; Chen, Yong-Xiong; Liu, Zu-Guo

2014-05-06

We investigated the therapeutic effects and underlying mechanisms of topical doxycycline in a benzalkonium chloride (BAC)-induced mouse dry eye model. Eye drops containing 0.025%, 0.1% doxycycline or solvent were administered to a BAC-induced dry eye model four times daily. The clinical evaluations, including tear break-up time (BUT), fluorescein staining, inflammatory index, and tear volume, were performed on days 0, 1, 4, 7, and 10. Global specimens were collected on day 10 and processed for immunofluorescent staining, TUNEL, and periodic acid-Schiff assay. The levels of inflammatory mediators in the corneas were determined by real-time PCR. The total and phosphorylated nuclear factor-κB (NF-κB) were detected by Western blot. Both 0.025% and 0.1% doxycycline treatments resulted in increased BUT, lower fluorescein staining scores, and inflammatory index on days 4, 7, and 10, while no significant change in tear volume was observed. The 0.1% doxycycline-treated group showed more improvements in decreasing fluorescein staining scores, increasing Ki-67-positive cells, and decreasing TUNEL- and keratin-10-positive cells than other groups. The mucin-filled goblet cells in conjunctivas were increased, and the expression of CD11b and levels of matrix metalloproteinase-9, IL-1β, IL-6, TNF-α, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant in corneas were decreased in both doxycycline-treated groups. In addition, doxycycline significantly reduced the phosphorylation of NF-κB activated in the BAC-treated corneas. Topical doxycycline showed clinical improvements and alleviated ocular surface inflammation on BAC-induced mouse dry eye, suggesting a potential as an anti-inflammatory agent in the clinical treatment of dry eye.

Phototoxicity of Doxycycline: A Systematic Review on Clinical Manifestations, Frequency, Cofactors, and Prevention.

PubMed

Goetze, Steven; Hiernickel, Christian; Elsner, Peter

2017-01-01

One of the most important dermatologic side effects of doxycycline is photosensitivity. As doxycycline is important for malaria prophylaxis and malaria is mainly spread in countries with high sun radiation, special attention should be paid to this adverse effect. While there are many publications on the phototoxicity of tetracyclines in general, only a few exist focusing on doxycycline. The objective of this systematic review was to summarize all available reports on clinical manifestations, influencing factors like UV dose or dose of medication, and the possibilities of prevention by sun protection. This review is based on a systematic search in PubMed for articles in English and German and a manual search between 1990 and 2015. The number of publications is low. Clinical symptoms vary from light sunburn-like sensation (burning, erythema) to large-area photodermatitis. Also, onycholysis is possible. The triggering UV spectrum seems to consist mainly of UVA1 (340-400 nm), so UV-protective products should be used that cover this range. Travelers to tropical countries taking doxycycline for malaria prophylaxis need thorough medical counseling to avoid possibly severe phototoxic reactions. Evidence base must be improved for giving advice on appropriate prevention measures to travelers taking doxycycline and having a risk of significant sun exposure. © 2017 S. Karger AG, Basel.

Effects of doxycycline on local and systemic inflammation in stable COPD patients, a randomized clinical trial.

PubMed

Prins, Hendrik J; Daniels, Johannes M A; Lindeman, Jan H; Lutter, René; Boersma, Wim G

2016-01-01

Neutrophilic inflammation plays a causal role in Chronic Obstructive Pulmonary Disease (COPD). Neutrophil derived myeloperoxidase(MPO) matrix metalloproteinases(MMP's), and elastases are thought to contribute to the perpetuation of the disease. The tetracycline analogue doxycycline has been shown to inhibit neutrophil-mediated inflammation. It was thus reasoned that doxycycline may attenuate neutrophil-mediated inflammation in COPD. In this double blind randomized controlled trial the effect of a 3-week course of doxycycline on sputum and systemic inflammatory parameters was evaluated in stable COPD patients. In order to exclude inflammation by bacterial colonisation patients must have 2 negative sputum cultures in the previous year. The effect of doxycycline treatment on inflammatory markers (TNF-α, IL-1β and IL-6) and neutrophil specific markers in sputum (MPO, MMP's, and IL-8) and serum C-reactive protein was evaluated. Sputum was obtained by sputum induction with hypertonic saline. A total of 41 patients were included. Ten patients were excluded as they were not able to produce sputum at the first or second visit. Baseline characteristics were similar in the two groups. In the remaining patients doxycycline did not influence sputum MPO concentrations. Also MMP-8 and 9, IL-6 and IL-8 concentrations as well as lung function parameters were not affected by doxycycline. Systemic inflammation by means of CRP was also not influenced by doxycycline. A three week course of doxycycline did not influence MPO sputum levels nor any of the other inflammatory sputum and systemic markers. ClinicalTrials.gov; No.: NCT00857038 URL: clinicaltrials.gov. Copyright © 2015 Elsevier Ltd. All rights reserved.

Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines.

PubMed

Zhao, Yan; Wang, Xinyu; Li, Lei; Li, Changzhong

2016-05-01

The clinical management of cervical cancer remains a challenge and the development of new treatment strategies merits attention. However, the discovery and development of novel compounds can be a long and labourious process. Drug repositioning may circumvent this process and facilitate the rapid translation of hypothesis-driven science into the clinics. In this work, we show that a FDA-approved antibiotic, doxycycline, effectively targets human papillomavirus (HPV) positive and negative cervical cancer cells in vitro and in vivo. Doxycycline significantly inhibits proliferation of a panel of cervical cancer cell lines. It also induces apoptosis of cervical cancer cells in a time- and dose-dependent manner. In addition, the apoptosis induced by doxycycline is through caspase-dependent pathway. Mechanism studies demonstrate that doxycycline affects oxygen consumption rate, glycolysis, and reduces ATP levels in cervical cancer cells. In HeLa xenograft mouse model, doxycycline significantly inhibits growth of tumour. Our in vitro and in vivo data clearly demonstrate the inhibitory effects of doxycycline on the growth and survival of cervical cancer cells. Our work provides the evidence that doxycycline can be repurposed for the treatment of cervical cancer and targeting energy metabolism may represent a potential therapeutic strategy for cervical cancer.

Controlled release of Doxycycline from gum acacia/poly(sodium acrylate) microparticles for oral drug delivery.

PubMed

Bajpai, S K; Jadaun, Mamta; Bajpai, M; Jyotishi, Pooja; Shah, Farhan Ferooz; Tiwari, Seema

2017-11-01

In the present work, Doxycycline loaded gum acacia (GA)/poly(sodium acrylate) (SA) hydrogels were prepared for the oral drug delivery of model drug Doxycycline. The hydrogels were characterized by X-ray diffraction analysis (XRD), Fourier transform infrared spectroscopy (FTIR) scanning electron microscopy (SEM) and Zeta potential. The dynamic release of Doxycycline was investigated in the physiological fluids at 37°C. Various kinetic models such as Power function model, Schott model and Higuchi model were applied to interpret the release data. Schott model was found to be most fitted. The Doxycycline loaded hydrogels were tested for their antibacterial action against E. coli. Copyright © 2017 Elsevier B.V. All rights reserved.

Doxycycline for Malaria Chemoprophylaxis and Treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis

PubMed Central

Tan, Kathrine R.; Magill, Alan J.; Parise, Monica E.; Arguin, Paul M.

2011-01-01

Doxycycline, a synthetically derived tetracycline, is a partially efficacious causal prophylactic (liver stage of Plasmodium) drug and a slow acting blood schizontocidal agent highly effective for the prevention of malaria. When used in conjunction with a fast acting schizontocidal agent, it is also highly effective for malaria treatment. Doxycycline is especially useful as a prophylaxis in areas with chloroquine and multidrug-resistant Plasmodium falciparum malaria. Although not recommended for pregnant women and children < 8 years of age, severe adverse events are rarely reported for doxycycline. This report examines the evidence behind current recommendations for the use of doxycycline for malaria and summarizes the available literature on its safety and tolerability. PMID:21460003

No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever.

PubMed

Todd, Suzanne R; Dahlgren, F Scott; Traeger, Marc S; Beltrán-Aguilar, Eugenio D; Marianos, Donald W; Hamilton, Charlene; McQuiston, Jennifer H; Regan, Joanna J

2015-05-01

To evaluate whether cosmetically relevant dental effects occurred among children who had received doxycycline for treatment of suspected Rocky Mountain spotted fever (RMSF). Children who lived on an American Indian reservation with high incidence of RMSF were classified as exposed or unexposed to doxycycline, based on medical and pharmacy record abstraction. Licensed, trained dentists examined each child's teeth and evaluated visible staining patterns and enamel hypoplasia. Objective tooth color was evaluated with a spectrophotometer. Fifty-eight children who received an average of 1.8 courses of doxycycline before 8 years of age and who now had exposed permanent teeth erupted were compared with 213 children who had never received doxycycline. No tetracycline-like staining was observed in any of the exposed children's teeth (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or hypoplasia (P=1.0) was found between the 2 groups. This study failed to demonstrate dental staining, enamel hypoplasia, or tooth color differences among children who received short-term courses of doxycycline at <8 years of age. Healthcare provider confidence in use of doxycycline for suspected RMSF in children may be improved by modifying the drug's label. Published by Elsevier Inc.

The role of doxycycline in the therapy of multidrug-resistant E. coli - an in vitro study.

PubMed

Lai, Chih-Cheng; Chen, Chi-Chung; Huang, Hui-Ling; Chuang, Yin-Ching; Tang, Hung-Jen

2016-08-18

This study assessed the in vitro antibacterial activity of combinations of amikacin and doxycycline or tigecycline against multidrug-resistant E. coli isolates. Twenty-four different pulsotypes, including 10 extended-spectrum β-lactamase (ESBL)-, 10 carbapenem-resistant, 2 New Delhi Metallo-beta-lactamase (NDM)- and 2 Klebsiella pneumoniae carbapenemase (KPC)-E. coli isolates were collected. All 24 isolates were susceptible to amikacin and tigecycline. Only 30% of ESBL and 50% of carbapenem-resistant E. coli were susceptible to doxycycline. Both of the NDM-E. coli had a MIC of 64 μg/ml. The checkerboard method showed that for the ESBL- and carbapenem-resistant E. coli, the synergistic effects of amikacin/doxycycline were 80% and 90%, respectively. For the two KPC- and two NDM-E. coli, the FIC index of amikacin/doxycycline were 0.5/0.375 and 0.5/0.281, respectively. For the ESBL- and carbapenem-resistant E. coli isolates, the combinations of amikacin and doxycycline exhibited synergistic activities against 80%, and 80% and 10% vs 60%, and 80% and 10% of the isolates at concentrations of 1x, 1/2x and 1/4xMIC, respectively. The synergistic effect seems to be similar for doxycycline and tigecycline based combinations with amikacin. In conclusion, the antibacterial activity of doxycycline can be enhanced by the addition of amikacin and is observed against most multidrug-resistant E. coli isolates.

A rapid and sensitive assay for determination of doxycycline using thioglycolic acid-capped cadmium telluride quantum dots

NASA Astrophysics Data System (ADS)

Tashkhourian, Javad; Absalan, Ghodratollah; Jafari, Marzieh; Zare, Saber

2016-01-01

A rapid, simple and inexpensive spectrofluorimetric sensor for determination of doxycycline based on its interaction with thioglycolic acid-capped cadmium telluride quantum dots (TGA/CdTe QDs) has been developed. Under the optimum experimental conditions, the sensor exhibited a fast response time of <10 s. The results revealed that doxycycline could quench the fluorescence of TGA/CdTe QDs via electron transfer from the QDs to doxycycline through a dynamic quenching mechanism. The sensor permitted determination of doxycycline in a concentration range of 1.9 × 10-6-6.1 × 10-5 mol L-1 with a detection limit of 1.1 × 10-7 mol L-1. The sensor was applied for determination of doxycycline in honey and human serum samples.

Suspected side effects of doxycycline use in dogs - a retrospective study of 386 cases.

PubMed

Schulz, B S; Hupfauer, S; Ammer, H; Sauter-Louis, C; Hartmann, K

2011-08-27

This study investigated doxycycline-related side effects in a large population of dogs. Data from 386 dogs that had received doxycycline for the treatment of various infectious diseases were analysed retrospectively. Potential side effects that developed during treatment were documented, and correlations with signalment, dose, duration of treatment, frequency of application, doxycycline preparation and use of additional drugs were investigated. Vomiting was reported in 18.3 per cent of dogs, 7.0 per cent developed diarrhoea and 2.5 per cent developed anorexia. While being treated with doxycycline, 39.4 per cent of dogs showed an increase in alanine aminotransferase (ALT) activity and 36.4 per cent showed an increase in alkaline phosphatase (ALP) activity. There was a dose-related risk of an increase in ALP activity (P=0.011, odds ratio [OR]=1.27, 95 per cent confidence interval [CI] 1.06 to 1.53), and older dogs treated with doxycycline were more likely to develop an increase in ALT activity (P=0.038, OR=1.23, 95 per cent CI 1.01 to 1.50) and vomiting (P=0.017, OR=1.11, 95 per cent CI 1.02 to 1.21).

Doxycycline in early CJD: a double-blinded randomised phase II and observational study.

PubMed

Varges, Daniela; Manthey, Henrike; Heinemann, Uta; Ponto, Claudia; Schmitz, Matthias; Schulz-Schaeffer, Walter J; Krasnianski, Anna; Breithaupt, Maren; Fincke, Fabian; Kramer, Katharina; Friede, Tim; Zerr, Inga

2017-02-01

The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD). From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival. Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)). On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD. EudraCT 2006-003934-14; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Characterization of interaction between doxycycline and human serum albumin by capillary electrophoresis-frontal analysis.

PubMed

Sun, Hanwen; He, Pan

2009-06-01

The binding of doxycycline to HSA under simulated physiological conditions (pH 7.4, 67 mM phosphate, I=0.17, drug concentration 100 microM, HSA concentration up to 475 microM, 36.5 degrees 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 x 10(3) M(-1) and 59.80%, respectively. In addition, the thermodynamic parameters including enthalpy change (DeltaH), entropy change (DeltaS) and free energy change (DeltaG) 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.

Assessment of solid microneedle rollers to enhance transmembrane delivery of doxycycline and inhibition of MMP activity.

PubMed

Omolu, Abbie; Bailly, Maryse; Day, Richard M

2017-11-01

Many chronic wounds exhibit high matrix metalloproteinase (MMP) activity that impedes the normal wound healing process. Intradermal delivery (IDD) of sub-antimicrobial concentrations of doxycycline, as an MMP inhibitor, could target early stages of chronic wound development and inhibit further wound progression. To deliver doxycycline intradermally, the skin barrier must be disrupted. Microneedle rollers offer a minimally invasive technique to penetrate the skin by creating multiple microchannels that act as temporary conduits for drugs to diffuse through. In this study, an innovative and facile approach for delivery of doxycycline across Strat-M TM membrane was investigated using microneedle rollers. The quantity and rate of doxycycline diffusing through the micropores directly correlated with increasing microneedle lengths (250, 500 and 750 μm). Treatment of Strat-M TM with microneedle rollers resulted in a reduction in fibroblast-mediated collagen gel contraction and MMP activity compared with untreated Strat-M TM . Our results show that treatment of an epidermal mimetic with microneedle rollers provides sufficient permeabilization for doxycycline diffusion and inhibition of MMP activity. We conclude that microneedle rollers are a promising, clinically ready tool suitable for delivery of doxycycline intradermally to treat chronic wounds.

Potential for Enhanced Therapeutic Activity of Biological Cancer Therapies with Doxycycline Combination

PubMed Central

Tang, Hui; Sampath, Padma; Yan, Xinmin; Thorne, Stephen H

2012-01-01

Despite significant strides made in the clinical translation of adoptive immune cell therapies, it is apparent that many tumors incorporate strategies to avoid recognition by receptors expressed on the immune cells, such as NKG2D. Strategies that stabilize the expression of ligands for these receptors may enhance the therapeutic potential of these and related therapies. Doxycycline inhibits matrix metalloproteinases (MMPs) that act to cleave the extracellular domain of MICA/B, ligands for the NKG2D receptor. Doxycycline treatment blocked shedding of MICA/B from a panel of human tumor cells, but also acted to increase their expression and cell surface translocation, possibly through its action on ATM. This meant that many tumor cells displayed increased MICA/B expression and enhanced susceptibility to CIK cells. Interestingly, doxycycline also selectively enhanced the replication of oncolytic vaccinia in many tumor cell lines, leading to increased sensitivity to these therapies. Combination (CIK-oncolytic vaccinia) therapies used in conjunction with doxycyline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and oncolytic viral therapies make it an excellent candidate for rapid clinical testing. PMID:23282955

Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

PubMed Central

Pulvino, Mary; Chen, Luojing; Oleksyn, David; Li, Jing; Compitello, George; Rossi, Randy; Spence, Stephen; Balakrishnan, Vijaya; Jordan, Craig; Poligone, Brian; Casulo, Carla; Burack, Richard; Shapiro, Joel L.; Bernstein, Steven; Friedberg, Jonathan W.; Deshaies, Raymond J.; Land, Hartmut; Zhao, Jiyong

2015-01-01

In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes. PMID:26142707

Clinical benefits of incorporating doxycycline into a canine heartworm treatment protocol.

PubMed

Nelson, C Thomas; Myrick, Elizabeth S; Nelson, Thomas A

2017-11-09

The objective of heartworm treatment is to improve the clinical condition of the patient and to eliminate pre-cardiac, juvenile, and adult worm stages with minimal complications. Pulmonary thromboembolisms are an inevitable consequence of worm death and can result in severe pulmonary reactions and even death of the patient. To minimize these reactions, various treatment protocols involving melarsomine, the only adulticidal drug approved by the US Food and Drug Administrations (FDA), in conjunction with macrocyclic lactone heartworm preventives and glucocorticosteroids have been advocated. The discovery of the bacterial endosymbiont Wolbachia in Dirofilaria immitis has led to several experimental studies examining the effects of administering doxycycline to reduce or eliminate Wolbachia organism. These studies have shown a decrease in gross and microscopic pathology of pulmonary parenchyma in experimental heartworm infections pretreated with doxycycline before melarsomine administration. Electronic medical records from a large veterinary practice in northeast Alabama were searched to identify dogs treated for heartworms with melarsomine from January 2005 through December 2012. The search was refined further to select for dogs that met the following criteria: 1) received two or three doses of ivermectin heartworm preventive prior to melarsomine injections, 2) received one injection of melarsomine followed by two injections 4 to 8 weeks later, and 3) were treated with prednisone following melarsomine injections. The dogs were then divided into those that also were treated with doxycycline 10 mg/kg BID for 4 weeks (Group A, n = 47) and those that did not receive doxycycline (Group B, n = 47). The medical notes of all 94 cases were then reviewed for comments concerning coughing, dyspnea, or hemoptysis in the history, physical exam template, or from telephone conversations with clients the week following each visit. Any dog that died within one year of treatment

A rapid and sensitive assay for determination of doxycycline using thioglycolic acid-capped cadmium telluride quantum dots.

PubMed

Tashkhourian, Javad; Absalan, Ghodratollah; Jafari, Marzieh; Zare, Saber

2016-01-05

A rapid, simple and inexpensive spectrofluorimetric sensor for determination of doxycycline based on its interaction with thioglycolic acid-capped cadmium telluride quantum dots (TGA/CdTe QDs) has been developed. Under the optimum experimental conditions, the sensor exhibited a fast response time of <10s. The results revealed that doxycycline could quench the fluorescence of TGA/CdTe QDs via electron transfer from the QDs to doxycycline through a dynamic quenching mechanism. The sensor permitted determination of doxycycline in a concentration range of 1.9×10(-6)-6.1×10(-5)molL(-1) with a detection limit of 1.1×10(-7)molL(-1). The sensor was applied for determination of doxycycline in honey and human serum samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Treatment of ocular rosacea: comparative study of topical cyclosporine and oral doxycycline.

PubMed

Arman, Aysegul; Demirseren, Duriye Deniz; Takmaz, Tamer

2015-01-01

To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints. One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups: nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline. Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes (P<0.001). Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs (P=0.01). There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group (P<0.05). Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.

Antibiotic susceptibility among Staphylococcus epidermidis isolated from prosthetic joint infections, with focus on doxycycline.

PubMed

Hamad, Tarza; Hellmark, Bengt; Nilsdotter-Augustinsson, Åsa; Söderquist, Bo

2015-12-01

In recent years, coagulase-negative staphylococci such as Staphylococcus epidermidis have gained importance as nosocomial pathogens, especially in immunocompromised patients and prosthetic joint infections (PJIs). These infections are often long lasting and difficult to treat due to the production of bacterial biofilm and the transformation of the bacteria into a stationary growth phase. Rifampicin is able to penetrate the biofilm, but to reduce the risk of development of rifampicin resistance it should be used in combination with an additional antibiotic. In this study we used Etest to investigate the antimicrobial susceptibility of 134 clinical isolates of S. epidermidis obtained from PJIs to six oral antibiotics: doxycycline, rifampicin, linezolid, fusidic acid, clindamycin, and ciprofloxacin. We also performed synergy testing on doxycycline in combination with each of the remaining antibiotics. Ninety-three (69%) of the 134 isolates were susceptible to doxycycline, 94/134 (70%) to rifampicin, 56/134 (42%) to clindamycin, 25/134 (19%) to ciprofloxacin, 81/134 (60%) to fusidic acid, and 100% to linezolid. Thirty-two (80%) of the 40 isolates not fully susceptible to rifampicin were susceptible to doxycycline. Doxycycline in combination with each of the other investigated antibiotics exerted an additive effect on nearly half of the isolates, with the exception of clindamycin, which displayed an even higher percentage of additive effect (69%). To conclude, as the majority of the S. epidermidis isolates were susceptible to doxycycline, this antimicrobial agent may provide a potential alternative for combination therapy together with rifampicin. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Effect of cathodic polarization on coating doxycycline on titanium surfaces.

PubMed

Geißler, Sebastian; Tiainen, Hanna; Haugen, Håvard J

2016-06-01

Cathodic polarization has been reported to enhance the ability of titanium based implant materials to interact with biomolecules by forming titanium hydride at the outermost surface layer. Although this hydride layer has recently been suggested to allow the immobilization of the broad spectrum antibiotic doxycycline on titanium surfaces, the involvement of hydride in binding the biomolecule onto titanium remains poorly understood. To gain better understanding of the influence this immobilization process has on titanium surfaces, mirror-polished commercially pure titanium surfaces were cathodically polarized in the presence of doxycycline and the modified surfaces were thoroughly characterized using atomic force microscopy, electron microscopy, secondary ion mass spectrometry, and angle-resolved X-ray spectroscopy. We demonstrated that no hydride was created during the polarization process. Doxycycline was found to be attached to an oxide layer that was modified during the electrochemical process. A bacterial assay using bioluminescent Staphylococcus epidermidis Xen43 showed the ability of the coating to reduce bacterial colonization and planktonic bacterial growth. Copyright © 2016 Elsevier B.V. All rights reserved.

Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

PubMed

Jung, Jae-Joon; Razavian, Mahmoud; Kim, Hye-Yeong; Ye, Yunpeng; Golestani, Reza; Toczek, Jakub; Zhang, Jiasheng; Sadeghi, Mehran M

2016-09-13

Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Currently, there is no non-invasive medical therapy for CAVD. Matrix metalloproteinases (MMPs) are upregulated in CAVD and play a role in its pathogenesis. Here, we evaluated the effect of doxycycline, a nonselective MMP inhibitor on CAVD progression in the mouse. Apolipoprotein (apo)E(-/-) mice (n = 20) were fed a Western diet (WD) to induce CAVD. After 3 months, half of the animals was treated with doxycycline, while the others continued WD alone. After 6 months, we evaluated the effect of doxycycline on CAVD progression by echocardiography, MMP-targeted micro single photon emission computed tomography (SPECT)/computed tomography (CT), and tissue analysis. Despite therapeutic blood levels, doxycycline had no significant effect on MMP activation, aortic valve leaflet separation or flow velocity. This lack of effect on in vivo images was confirmed on tissue analysis which showed a similar level of aortic valve gelatinase activity, and inflammation between the two groups of animals. In conclusion, doxycycline (100 mg/kg/day) had no effect on CAVD progression in apoE(-/-) mice with early disease. Studies with more potent and specific inhibitors are needed to establish any potential role of MMP inhibition in CAVD development and progression.

The end of a dogma: the safety of doxycycline use in young children for malaria treatment.

PubMed

Gaillard, Tiphaine; Briolant, Sébastien; Madamet, Marylin; Pradines, Bruno

2017-04-13

Anti-malarial drug resistance to chloroquine and sulfadoxine-pyrimethamine has spread from Southeast Asia to Africa. Furthermore, the recent emergence of resistance to artemisinin-based combination therapy (ACT) in Southeast Asia highlights the need to identify new anti-malarial drugs. Doxycycline is recommended for malaria chemoprophylaxis for travel in endemic areas, or in combination with the use of quinine for malaria treatment when ACT is unavailable or when the treatment of severe malaria with artesunate fails. However, doxycycline is not used in young children under 8 years of age due to its contraindication due to the risk of yellow tooth discolouration and dental enamel hypoplasia. Doxycycline was developed after tetracycline and was labelled with the same side-effects as the earlier tetracyclines. However, recent studies report little or no effects of doxycycline on tooth staining or dental enamel hypoplasia in children under 8 years of age. In the United States, the Centers for Disease Control and Prevention have recommended the use of doxycycline for the treatment of acute and chronic Q fever and tick-borne rickettsial diseases in young children. It is time to rehabilitate doxycycline and to recommend it for malaria treatment in children under 8 years of age.

Molecular effects of doxycycline treatment on pterygium as revealed by massive transcriptome sequencing.

PubMed

Larráyoz, Ignacio M; de Luis, Alberto; Rúa, Oscar; Velilla, Sara; Cabello, Juan; Martínez, Alfredo

2012-01-01

Pterygium is a lesion of the eye surface which involves cell proliferation, migration, angiogenesis, fibrosis, and extracellular matrix remodelling. Surgery is the only approved method to treat this disorder, but high recurrence rates are common. Recently, it has been shown in a mouse model that treatment with doxycycline resulted in reduction of the pterygium lesions. Here we study the mechanism(s) of action by which doxycycline achieves these results, using massive sequencing techniques. Surgically removed pterygia from 10 consecutive patients were set in short term culture and exposed to 0 (control), 50, 200, and 500 µg/ml doxycycline for 24 h, their mRNA was purified, reverse transcribed and sequenced through Illumina's massive sequencing protocols. Acquired data were subjected to quantile normalization and analyzed using cytoscape plugin software to explore the pathways involved. False discovery rate (FDR) methods were used to identify 332 genes which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors. A high correlation was obtained when comparing ultrasequencing data with qRT-PCR and ELISA results. Doxycycline significantly modified the expression of important cellular pathways in pterygium cells, in a way which is consistent with the observed efficacy of this antibiotic to reduce pterygium lesions in a mouse model. Clinical trials are under way to demonstrate whether there is a benefit for human patients.

Stability of Doxycycline in Feed and Water and Minimal Effective Doses in Tetracycline-Inducible Systems

PubMed Central

Redelsperger, Irka M; Taldone, Tony; Riedel, Elyn R; Lepherd, Michelle L; Lipman, Neil S; Wolf, Felix R

2016-01-01

Despite the extensive use of doxycycline in tetracycline-inducible rodent models, little is known regarding its stability in feed or water or the most effective route or dose. We assessed the concentrations of doxycycline in reverse-osmosis–purified (RO; pH 6.0) and acidified RO (pH 2.6) water in untinted or green-tinted bottles. Doxycycline remained stable in all groups for 7 d and in acidified water in untinted bottles for 14 d. Fungal growth occurred in nonacidified water in tinted and untinted bottles by 12 and 14 d, respectively, and in tinted bottles containing acidified water on day 14, but not in untinted bottles with acidified water. Doxycycline concentrations were also assessed before and at various points after the pelleting of feed from 2 vendors. Each batch was divided for storage at 4 °C, at room temperature, or within ventilated mouse isolator cages and then sampled monthly for 6 mo. Drying caused the greatest decline in doxycycline concentration, whereas γ-irradiation plus shipping and storage condition had minimal effect. Two mouse lines with tetracycline-inducible promoters received 25, 150, or 467 µg/mL or 2 mg/mL doxycycline in water and 200 or 625 ppm in feed before analysis of GFP expression. GFP was expressed in Rosa-rtTA2 mice at 150 µg/mL, whereas Cags-rtTA3 mice required 25 µg/mL. These studies indicate that 1) doxycycline-compounded feed can be handled in the same manner as standard rodent feed, 2) tinted water bottles are not necessary for maintaining drug concentrations, and 3) concentrations lower than those used typically may be effective in lines with tetracycline-inducible promoters. PMID:27423155

Cooperation of Doxycycline with Phytochemicals and Micronutrients Against Active and Persistent Forms of Borrelia sp.

PubMed

Goc, Anna; Niedzwiecki, Alexandra; Rath, Matthias

2016-01-01

Phytochemicals and micronutrients represent a growing theme in antimicrobial defense; however, little is known about their anti-borreliae effects of reciprocal cooperation with antibiotics. A better understanding of this aspect could advance our knowledge and help improve the efficacy of current approaches towards Borrelia sp. In this study, phytochemicals and micronutrients such as baicalein, luteolin, 10-HAD, iodine, rosmarinic acid, and monolaurin, as well as, vitamins D3 and C were tested in a combinations with doxycycline for their in vitro effectiveness against vegetative (spirochetes) and latent (rounded bodies, biofilm) forms of Borrelia burgdorferi and Borrelia garinii. Anti-borreliae effects were evaluated according to checkerboard assays and supported by statistical analysis. The results showed that combination of doxycycline with flavones such as baicalein and luteolin exhibited additive effects against all morphological forms of studied Borrelia sp. Doxycycline combined with iodine demonstrated additive effects against spirochetes and biofilm, whereas with fatty acids such as monolaurin and 10-HAD it produced FICIs of indifference. Additive anti-spirochetal effects were also observed when doxycycline was used with rosmarinic acid and both vitamins D3 and C. Antagonism was not observed in any of the cases. This data revealed the intrinsic anti-borreliae activity of doxycycline with tested phytochemicals and micronutrients indicating that their addition may enhance efficacy of this antibiotic in combating Borrelia sp. Especially the addition of flavones balcalein and luteolin to a doxycycline regimen could be explored further in defining more effective treatments against these bacteria.

Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

PubMed Central

Kroon, Albert M.; Taanman, Jan-Willem

2015-01-01

Most reported studies with animal models of abdominal aortic aneurysm (AAA) and several studies with patients have suggested that doxycycline favourably modifies AAA; however, a recent large long-term clinical trial found that doxycycline did not limit aneurysm growth. Thus, there is currently no convincing evidence that doxycycline reduces AAA expansion. Here, we critically review the available experimental and clinical information about the effects of doxycycline when used as a pharmacological treatment for AAA. The view that AAA can be considered an autoimmune disease and the observation that AAA tissue shows clonal expansion of T cells is placed in the light of the well-known inhibition of mitochondrial protein synthesis by doxycycline. In T cell leukaemia animal models, this inhibitory effect of the antibiotic has been shown to impede T cell proliferation, resulting in complete tumour eradication. We suggest that the available evidence of doxycycline action on AAA is erroneously ascribed to its inhibition of matrix metalloproteinases (MMPs) by competitive binding of the zinc ion co-factor. Although competitive binding may explain the inhibition of proteolytic activity, it does not explain the observed decreases of MMP mRNA levels. We propose that the observed effects of doxycycline are secondary to inhibition of mitochondrial protein synthesis. Provided that serum doxycycline levels are kept at adequate levels, the inhibition will result in a proliferation arrest, especially of clonally expanding T cells. This, in turn, leads to the decrease of proinflammatory cytokines that are normally generated by these cells. The drastic change in cell type composition may explain the changes in MMP mRNA and protein levels in the tissue samples. PMID:25993290

The Effect of a Common Antibiotics Doxycycline on Non-Healing Chronic Wound.

PubMed

Xu, Dixon H; Zhu, Ziwen; Fang, Yujiang

2017-01-01

Up to 25% of diabetic patients will develop a diabetic foot ulcer. Chronic wounds such as diabetic foot ulcers often fail to heal with conventional therapies. In recent years, it has been identified that chronic wounds are usually associated with elevated level of matrix metalloproteinases (MMPs). Doxycycline, a cheap tetracycline antibiotic, has been shown to inhibit MMPs both in vitro and in vivo independent of its antimicrobial property. We undertook a search through PUBMED for peer-reviewed research literature with doxycycline, chronic wound, diabetes, MMPs as key words. Seventy papers were included in the review. This review identified doxycycline is a very promising drug to be used in patients with diabetic foot ulcers because higher efficacy even in a very low dosage, little side effects in a lower dosage, inhibition of MMP as well as prevention/treatment of infection in the ulcers, beneficial to cardiovascular complications and cheap to manufacture. In this review, we provide an overview of the roles of MMPs in the pathogenesis of chronic wounds and explore the potential application of doxycycline as a treatment option in managing chronic wounds such as diabetic foot ulcers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-κB activation.

PubMed

Tang, Xiaoyun; Wang, Xianyan; Zhao, Yuan Y; Curtis, Jonathan M; Brindley, David N

2017-02-08

We previously discovered that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells. These enzymes degrade circulating lysophosphatidate and therefore doxycycline increases the turnover of plasma lysophosphatidate and decreases its concentration. Extracellular lysophosphatidate signals through six G protein-coupled receptors and it is a potent promoter of tumor growth, metastasis and chemo-resistance. These effects depend partly on the stimulation of inflammation that lysophosphatidate produces. In this work, we used a syngeneic orthotopic mouse model of breast cancer to determine the impact of doxycycline on circulating lysophosphatidate concentrations and tumor growth. Cytokine/chemokine concentrations in tumor tissue and plasma were measured by multiplexing laser bead technology. Leukocyte infiltration in tumors was analyzed by immunohistochemistry. The expression of IL-6 in breast cancer cell lines was determined by RT-PCR. Cell growth was measured in Matrigel™ 3D culture. The effects of doxycycline on NF-κB-dependent signaling were analyzed by Western blotting. Doxycycline decreased plasma lysophosphatidate concentrations, delayed tumor growth and decreased the concentrations of several cytokines/chemokines (IL-1β, IL-6, IL-9, CCL2, CCL11, CXCL1, CXCL2, CXCL9, G-CSF, LIF, VEGF) in the tumor. These results were compatible with the effects of doxycycline in decreasing the numbers of F4/80 + macrophages and CD31 + blood vessel endothelial cells in the tumor. Doxycycline also decreased the lysophosphatidate-induced growth of breast cancer cells in three-dimensional culture. Lysophosphatidate-induced Ki-67 expression was inhibited by doxycycline. NF-κB activity in HEK293 cells transiently expressing a NF-κB-luciferase reporter vectors was also inhibited by doxycycline. Treatment of breast cancer cells with doxycycline also decreased the translocation of NF-κB to the nucleus and the mRNA levels for IL-6 in the presence

Wolbachia, doxycycline and macrocyclic lactones: New prospects in the treatment of canine heartworm disease.

PubMed

Kramer, L; Crosara, S; Gnudi, G; Genchi, M; Mangia, C; Viglietti, A; Quintavalla, C

2018-04-30

Melarsomine dihydrochloride (Immiticide®, Merial) is the only approved adulticidal drug for the treatment of canine heartworm disease (HWD). However, in cases where arsenical therapy is not possible or is contraindicated, a monthly heartworm preventive along with doxycycline for a 4-week period, which targets the bacterial endosymbiont Wolbachia, might be considered. There are published reports on the efficacy of ivermectin and doxycycline in both experimentally and naturally infected dogs, but no data on the use of other macrocyclic lactones (MLs) with a similar treatment regime. Preliminary results of studies in dogs show that a topical formulation of moxidectin, the only ML currently registered as a microfilaricide, is also adulticidal when combined with doxycycline. It is not yet known if the efficacy of these combination therapies is due to pharmacokinetic synergism. A recent study showed that serum levels of doxycycline in dogs treated with the combination protocol were not statistically different compared to dogs treated with doxycycline alone. However, lungs from dogs treated with the combination therapy showed a marked reduction in T regulatory cells, indicating that treatment efficacy may be due to a heightened immune response against the parasite. Further studies are necessary to evaluate the long-term clinical outcome of combination protocols and to establish the most efficient treatment for HWD in dogs. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

76 FR 44926 - Renewal of Declaration Regarding Emergency Use of Doxycycline Hyclate Tablets Accompanied by...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-27

... Emergency Use of Doxycycline Hyclate Tablets Accompanied by Emergency Use Information and Amendment To... hyclate tablets accompanied by emergency use information subject to the terms of any authorization issued... authorization of the emergency use of doxycycline hyclate tablets accompanied by emergency use information...

Metabolic Abnormalities Detected in Phase II Evaluation of Doxycycline in Dogs with Multicentric B-Cell Lymphoma.

PubMed

Hume, Kelly R; Sylvester, Skylar R; Borlle, Lucia; Balkman, Cheryl E; McCleary-Wheeler, Angela L; Pulvino, Mary; Casulo, Carla; Zhao, Jiyong

2018-01-01

Doxycycline has antiproliferative effects in human lymphoma cells and in murine xenografts. We hypothesized that doxycycline would decrease canine lymphoma cell viability and prospectively evaluated its clinical tolerability in client-owned dogs with spontaneous, nodal, multicentric, substage a, B-cell lymphoma, not previously treated with chemotherapy. Treatment duration ranged from 1 to 8 weeks (median and mean, 3 weeks). Dogs were treated with either 10 ( n  = 6) or 7.5 ( n  = 7) mg/kg by mouth twice daily. One dog had a stable disease for 6 weeks. No complete or partial tumor responses were observed. Five dogs developed grade 3 and/or 4 metabolic abnormalities suggestive of hepatopathy with elevations in bilirubin, ALT, ALP, and/or AST. To evaluate the absorption of oral doxycycline in our study population, serum concentrations in 10 treated dogs were determined using liquid chromatography tandem mass spectrometry. Serum levels were variable and ranged from 3.6 to 16.6 µg/ml (median, 7.6 µg/ml; mean, 8.8 µg/ml). To evaluate the effect of doxycycline on canine lymphoma cell viability in vitro , trypan blue exclusion assay was performed on canine B-cell lymphoma cell lines (17-71 and CLBL) and primary B-cell lymphoma cells from the nodal tissue of four dogs. A doxycycline concentration of 6 µg/ml decreased canine lymphoma cell viability by 80%, compared to matched, untreated, control cells (mixed model analysis, p  < 0.0001; Wilcoxon signed rank test, p  = 0.0313). Although the short-term administration of oral doxycycline is not associated with the remission of canine lymphoma, combination therapy may be worthwhile if future research determines that doxycycline can alter cell survival pathways in canine lymphoma cells. Due to the potential for metabolic abnormalities, close monitoring is recommended with the use of this drug in tumor-bearing dogs. Additional research is needed to assess the tolerability of chronic doxycycline

Metabolic Abnormalities Detected in Phase II Evaluation of Doxycycline in Dogs with Multicentric B-Cell Lymphoma

PubMed Central

Hume, Kelly R.; Sylvester, Skylar R.; Borlle, Lucia; Balkman, Cheryl E.; McCleary-Wheeler, Angela L.; Pulvino, Mary; Casulo, Carla; Zhao, Jiyong

2018-01-01

Doxycycline has antiproliferative effects in human lymphoma cells and in murine xenografts. We hypothesized that doxycycline would decrease canine lymphoma cell viability and prospectively evaluated its clinical tolerability in client-owned dogs with spontaneous, nodal, multicentric, substage a, B-cell lymphoma, not previously treated with chemotherapy. Treatment duration ranged from 1 to 8 weeks (median and mean, 3 weeks). Dogs were treated with either 10 (n = 6) or 7.5 (n = 7) mg/kg by mouth twice daily. One dog had a stable disease for 6 weeks. No complete or partial tumor responses were observed. Five dogs developed grade 3 and/or 4 metabolic abnormalities suggestive of hepatopathy with elevations in bilirubin, ALT, ALP, and/or AST. To evaluate the absorption of oral doxycycline in our study population, serum concentrations in 10 treated dogs were determined using liquid chromatography tandem mass spectrometry. Serum levels were variable and ranged from 3.6 to 16.6 µg/ml (median, 7.6 µg/ml; mean, 8.8 µg/ml). To evaluate the effect of doxycycline on canine lymphoma cell viability in vitro, trypan blue exclusion assay was performed on canine B-cell lymphoma cell lines (17-71 and CLBL) and primary B-cell lymphoma cells from the nodal tissue of four dogs. A doxycycline concentration of 6 µg/ml decreased canine lymphoma cell viability by 80%, compared to matched, untreated, control cells (mixed model analysis, p < 0.0001; Wilcoxon signed rank test, p = 0.0313). Although the short-term administration of oral doxycycline is not associated with the remission of canine lymphoma, combination therapy may be worthwhile if future research determines that doxycycline can alter cell survival pathways in canine lymphoma cells. Due to the potential for metabolic abnormalities, close monitoring is recommended with the use of this drug in tumor-bearing dogs. Additional research is needed to assess the tolerability of chronic doxycycline therapy

Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer.

PubMed

Zhang, Le; Xu, Liang; Zhang, Fengchun; Vlashi, Erina

2017-04-18

Experimental evidence suggest that breast tumors originate from breast cancer stem cells (BCSCs), and that mitochondrial biogenesis is essential for the anchorage-independent clonal expansion and survival of CSCs, thus rendering mitochondria a significant target for novel treatment approaches. One of the recognized side effects of the FDA-approved drug, doxycycline is the inhibition of mitochondrial biogenesis. Here we investigate the mechanism by which doxycycline exerts its inhibitory effects on the properties of breast cancer cells and BCSCs, such as mammosphere forming efficiency, invasion, migration, apoptosis, the expression of stem cell markers and epithelial-to-mesenchymal transition (EMT) related markers of breast cancer cells. In addition, we explored whether autophagy plays a role in the inhibitory effect of doxycycline on breast cancer cells. We find that doxycyline can inhibit the viability and proliferation of breast cancer cells and BCSCs, decrease mammosphere forming efficiency, migration and invasion, and EMT of breast cancer cells. Expression of stem cell factors Oct4, Sox2, Nanog and CD44 were also significantly downregulated after doxycycline treatment. Moreover, doxycycline could down-regulate the expression of the autophagy marker LC-3BI and LC-3BII, suggesting that inhibiting autophagy may be responsible in part for the observed effects on proliferation, EMT and stem cell markers. The potent inhibition of EMT and cancer stem-like characteristics in breast cancer cells by doxycycline treatment suggests that this drug can be repurposed as an anti-cancer drug in the treatment of breast cancer patients in the clinic.

Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer

PubMed Central

Xu, Liang; Zhang, Fengchun; Vlashi, Erina

2017-01-01

ABSTRACT Experimental evidence suggest that breast tumors originate from breast cancer stem cells (BCSCs), and that mitochondrial biogenesis is essential for the anchorage-independent clonal expansion and survival of CSCs, thus rendering mitochondria a significant target for novel treatment approaches. One of the recognized side effects of the FDA-approved drug, doxycycline is the inhibition of mitochondrial biogenesis. Here we investigate the mechanism by which doxycycline exerts its inhibitory effects on the properties of breast cancer cells and BCSCs, such as mammosphere forming efficiency, invasion, migration, apoptosis, the expression of stem cell markers and epithelial-to-mesenchymal transition (EMT) related markers of breast cancer cells. In addition, we explored whether autophagy plays a role in the inhibitory effect of doxycycline on breast cancer cells. We find that doxycyline can inhibit the viability and proliferation of breast cancer cells and BCSCs, decrease mammosphere forming efficiency, migration and invasion, and EMT of breast cancer cells. Expression of stem cell factors Oct4, Sox2, Nanog and CD44 were also significantly downregulated after doxycycline treatment. Moreover, doxycycline could down-regulate the expression of the autophagy marker LC-3BI and LC-3BII, suggesting that inhibiting autophagy may be responsible in part for the observed effects on proliferation, EMT and stem cell markers. The potent inhibition of EMT and cancer stem-like characteristics in breast cancer cells by doxycycline treatment suggests that this drug can be repurposed as an anti-cancer drug in the treatment of breast cancer patients in the clinic. PMID:27753527

Systemic antibiotic prophylaxis prior to gastrointestinal surgery - is oral administration of doxycycline and metronidazole adequate?

PubMed

Giske, Anneli; Nymo, Linn Såve; Fuskevåg, Ole-Martin; Amundsen, Siri; Simonsen, Gunnar Skov; Lassen, Kristoffer

Antibiotic prophylaxis is recommended prior to a wide range of gastrointestinal operations to reduce the rate of surgical site infections (SSIs). Traditional intravenous (IV) drugs are costly and their preparation strains nursing resources at the wards. While oral administration may attenuate these limitations, its use remains limited. We aimed to assess whether a dual oral antibiotic prophylaxis regimen provides adequate serum concentrations throughout the surgical procedure. We measured serum concentrations of doxycycline and metronidazole following single oral doses of 400 mg doxycycline and 1200 mg metronidazole at first incision and repeated at wound closure in a cohort of patients undergoing elective gastrointestinal surgery. Both drugs were dispensed at least two hours before skin incision. Serum concentrations were compared to minimum inhibitory concentrations (MIC) and epidemiological cut-off values (ECOFFs) for relevant pathogens. Mean serum concentrations of doxycycline at first incision and at wound closure were 5.75 mg/L and 4.66 mg/L and of metronidazole 18.88 mg/L and 15.56 mg/L, respectively. Metronidazole concentrations were above ECOFF (2 mg/L) for relevant anaerobic species in 103/104 of patients in both samples. Doxycycline serum concentrations were above the ECOFF for common Enterobacteriaceae species (4 mg/L) in both samples in 58/104 patients (55.8%). A single dose of orally administered metronidazole provides adequate concentrations throughout surgery in a heterogeneous cohort of patients. Uncertainty persists regarding the adequacy of doxycycline concentrations, as the optimal serum level of doxycycline in a prophylactic setting has not been established.

In Vitro Adsorption and in Vivo Pharmacokinetic Interaction between Doxycycline and Frequently Used Mycotoxin Binders in Broiler Chickens.

PubMed

De Mil, Thomas; Devreese, Mathias; Broekaert, Nathan; Fraeyman, Sophie; De Backer, Patrick; Croubels, Siska

2015-05-06

Mycotoxin binders are readily mixed in feeds to prevent uptake of mycotoxins by the animal. Concerns were raised for nonspecific binding with orally administered veterinary drugs by the European Food Safety Authority in 2010. This paper describes the screening for in vitro adsorption of doxycycline-a broad-spectrum tetracycline antibiotic-to six different binders that were able to bind >75% of the doxycycline. Next, an in vivo pharmacokinetic interaction study of doxycycline with two of the binders, which demonstrated significant in vitro binding, was performed in broiler chickens using an oral bolus model. It was shown that two montmorillonite-based binders were able to lower the area under the plasma concentration-time curve of doxycycline by >60% compared to the control group. These results may indicate a possible risk for reduced efficacy of doxycycline when used concomitantly with montmorillonite-based mycotoxin binders.

Doxycycline shows dose-dependent changes in hernia repair strength after mesh repair.

PubMed

Tharappel, Job C; Harris, Jennifer W; Zwischenberger, Brittany A; Levy, Salomon M; Puleo, David A; Roth, J Scott

2016-05-01

Ventral hernia is a commonly occurring surgical problem. Our earlier studies have shown that a 30 mg/kg dose of doxycycline can significantly impact the strength of polypropylene (PP) mesh in a rat hernia repair model at 6 and 12 weeks. The objective of the present study was to investigate the dose dependence of doxycycline treatment on hernia repair strengths in rats. Fifty-six Sprague-Dawley rats underwent hernia repair with either PP mesh (n = 28) or sutures only (primary; n = 28); both groups were further divided into four doxycycline groups of seven animals each: control (0 mg/kg), low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg). One day before hernia repair surgery, animals received doxycycline doses by gavage and continued receiving daily until euthanasia. After 8 weeks, rats were euthanized and tissue samples from hernia repaired area were collected and analyzed for tensile strength using a tensiometer (Instron, Canton, MA, USA), while MMPs 2, 3, and 9, and collagen type 1 and 3 were analyzed by western blotting. In mesh-repaired animals, medium and high doxycycline dose repaired mesh fascia interface (MFI) showed significant increase in tensile strength when compared to control. In the primary repaired animals, there was no significant difference in MFI tensile strength in any dose group. In medium-dose MFI, there was a significant reduction in MMPs 2, 3, and 9. In this animal group, MFI showed significant increase in collagen 1 and significant reduction in collagen type 3 when compared to control. It is possible to improve the strength of mesh-repaired tissue by administering a significantly lower dose of the drug, which has implications for translation of the findings.

Doxycycline supplementation allows for the culture of human ESCs/iPSCs with media changes at 3-day intervals.

PubMed

Chang, Mi-Yoon; Oh, Boram; Rhee, Yong-Hee; Lee, Sang-Hun

2015-11-01

Culturing human embryonic stem and induced pluripotent stem cells (hESCs/iPSCs) is one of the most costly and labor-intensive tissue cultures, as media containing expensive factors/cytokines should be changed every day to maintain and propagate undifferentiated hESCs/iPSCs in vitro. We recently reported that doxycycline, an anti-bacterial agent, had dramatic effects on hESC/iPSC survival and promoted self-renewal. In this study, we extended the effects of doxycycline to a more practical issue to save cost and labor in hESC/iPSC cultures. Regardless of cultured cell conditions, hESCs/iPSCs in doxycycline-supplemented media were viable and proliferating for at least 3 days without media change, while none or few viable cells were detected in the absence of doxycycline in the same conditions. Thus, hESCs/iPSCs supplemented with doxycycline can be cultured for a long period of time with media changes at 3-day intervals without altering their self-renewal and pluripotent properties, indicating that doxycycline supplementation can reduce the frequency of media changes and the amount of media required by 1/3. These findings strongly encourage the use of doxycycline to save cost and labor in culturing hESCs/iPSCs. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Effect of doxycycline on epithelial-mesenchymal transition via the p38/Smad pathway in respiratory epithelial cells.

PubMed

Shin, Jae-Min; Kang, Ju-Hyung; Lee, Seoung-Ae; Park, Il-Ho; Lee, Heung-Man

2017-03-01

Doxycycline has antibacterial and anti-inflammatory effects, and it also suppresses collagen biosynthesis. This study aimed to confirm the effects and mechanism of doxycycline on transforming growth factor (TGF) beta 1 induced epithelial-mesenchymal transition and cell migration in A549 and primary nasal epithelial cells. A 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay and phalloidin-fluorescein isothiocyanate staining were used to evaluate cytotoxicity and cellular morphologic changes. Western blot and immunofluorescence staining were used to determine the expression levels of E-cadherin, vimentin, alpha-smooth muscle actin, fibronectin, phosphorylated Smad2/3, and mitogen-activated protein kinases. Scratch and transwell migration assays were used to assess cellular migration ability. Doxycycline (0-10 μg/mL) had no significant cytotoxic effects in A549 and primary nasal epithelial cells. Increased expression of mesenchymal markers, including vimentin, alpha-smooth muscle actin, and fibronectin in TGF beta 1 induced A549 cells were downregulated by doxycycline treatment. In contrast, E-cadherin expression was upregulated in TGF beta 1 induced A549 cells. An in vitro cell migration assay showed that doxycycline also inhibited the ability of TGF beta 1 induced migration. Doxycycline treatment suppressed the activation of Smad2/3 and p38, whereas its inhibitory effects were similar to each element-specific inhibitor in A549 and primary nasal epithelial cells. Doxycycline inhibited TGF beta 1 induced epithelial-to-mesenchymal transition and migration by targeting Smad2/3 and p38 signal pathways in respiratory epithelial cells.

Doxycycline reduces the migration of tuberous sclerosis complex-2 null cells - effects on RhoA-GTPase and focal adhesion kinase

PubMed Central

Ng, Ho Yin; Oliver, Brian Gregory George; Burgess, Janette Kay; Krymskaya, Vera P; Black, Judith Lee; Moir, Lyn M

2015-01-01

Lymphangioleiomyomatosis (LAM) is associated with dysfunction of the tuberous sclerosis complex (TSC) leading to enhanced cell proliferation and migration. This study aims to examine whether doxycycline, a tetracycline antibiotic, can inhibit the enhanced migration of TSC2-deficient cells, identify signalling pathways through which doxycycline works and to assess the effectiveness of combining doxycycline with rapamycin (mammalian target of rapamycin complex 1 inhibitor) in controlling cell migration, proliferation and wound closure. TSC2-positive and TSC2-negative mouse embryonic fibroblasts (MEF), 323-TSC2-positive and 323-TSC2-null MEF and Eker rat uterine leiomyoma (ELT3) cells were treated with doxycycline or rapamycin alone, or in combination. Migration, wound closure and proliferation were assessed using a transwell migration assay, time-lapse microscopy and manual cell counts respectively. RhoA-GTPase activity, phosphorylation of p70S6 kinase (p70S6K) and focal adhesion kinase (FAK) in TSC2-negative MEF treated with doxycycline were examined using ELISA and immunoblotting techniques. The enhanced migration of TSC2-null cells was reduced by doxycycline at concentrations as low as 20 pM, while the rate of wound closure was reduced at 2–59 μM. Doxycycline decreased RhoA-GTPase activity and phosphorylation of FAK in these cells but had no effect on the phosphorylation of p70S6K, ERK1/2 or AKT. Combining doxycycline with rapamycin significantly reduced the rate of wound closure at lower concentrations than achieved with either drug alone. This study shows that doxycycline inhibits TSC2-null cell migration. Thus doxycycline has potential as an anti-migratory agent in the treatment of diseases with TSC2 dysfunction. PMID:26282580

Doxycycline reduces the migration of tuberous sclerosis complex-2 null cells - effects on RhoA-GTPase and focal adhesion kinase.

PubMed

Ng, Ho Yin; Oliver, Brian Gregory George; Burgess, Janette Kay; Krymskaya, Vera P; Black, Judith Lee; Moir, Lyn M

2015-11-01

Lymphangioleiomyomatosis (LAM) is associated with dysfunction of the tuberous sclerosis complex (TSC) leading to enhanced cell proliferation and migration. This study aims to examine whether doxycycline, a tetracycline antibiotic, can inhibit the enhanced migration of TSC2-deficient cells, identify signalling pathways through which doxycycline works and to assess the effectiveness of combining doxycycline with rapamycin (mammalian target of rapamycin complex 1 inhibitor) in controlling cell migration, proliferation and wound closure. TSC2-positive and TSC2-negative mouse embryonic fibroblasts (MEF), 323-TSC2-positive and 323-TSC2-null MEF and Eker rat uterine leiomyoma (ELT3) cells were treated with doxycycline or rapamycin alone, or in combination. Migration, wound closure and proliferation were assessed using a transwell migration assay, time-lapse microscopy and manual cell counts respectively. RhoA-GTPase activity, phosphorylation of p70S6 kinase (p70S6K) and focal adhesion kinase (FAK) in TSC2-negative MEF treated with doxycycline were examined using ELISA and immunoblotting techniques. The enhanced migration of TSC2-null cells was reduced by doxycycline at concentrations as low as 20 pM, while the rate of wound closure was reduced at 2-59 μM. Doxycycline decreased RhoA-GTPase activity and phosphorylation of FAK in these cells but had no effect on the phosphorylation of p70S6K, ERK1/2 or AKT. Combining doxycycline with rapamycin significantly reduced the rate of wound closure at lower concentrations than achieved with either drug alone. This study shows that doxycycline inhibits TSC2-null cell migration. Thus doxycycline has potential as an anti-migratory agent in the treatment of diseases with TSC2 dysfunction. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Doxycycline reduces nitric oxide production in guinea pig inner ears.

PubMed

Helling, Kai; Wodarzcyk, Karl; Brieger, Jürgen; Schmidtmann, Irene; Li, Huige; Mann, Wolf J; Heinrich, Ulf-Rüdiger

2011-12-01

Gentamicin application is an important therapeutic option to control vertigo spells in Ménière's disease. However, even in the case of low-dose intratympanic application, gentamicin might contribute to a pathological NO-increase leading to cochlear damage and hearing impairment. The study was performed to evaluate the nitric oxide (NO) reducing capacity of doxycycline in the inner ear after NO-induction by gentamicin. In a prospective animal study, a single dose of gentamicin (10mg/kg body weight) was injected intratympanically into male guinea pigs (n=48). The auditory brainstem responses (ABRs) were recorded prior to application and 3, 5 and 7 days afterwards. The organ of Corti and the lateral wall of 42 animals were isolated after 7 days and incubated separately for 6h in cell culture medium. Doxycycline was adjusted to organ cultures of 5 animals. Two NOS inhibitors, N(G)-Nitro-l-arginine methyl ester (l-NAME) and NG-monomethyl-l-arginine monoacetate (l-NMMA), were applied in three different concentrations to the organ cultures of 30 animals in total (5 animals per concentration). As controls, seven animals received no further substance except gentamicin. The NO-production was quantified by chemiluminescence. Additional six gentamicin-treated animals were used for immunohistochemical studies. The ABRs declined continuously from the first to the seventh day after gentamicin application. Doxycycline reduced NO-production in the lateral wall by 54% (p=.029) comparable to the effect of the applied nitric oxide inhibitors. In the organ of Corti, NO-production was reduced by about 41% showing no statistical significance in respect to great inter-animal variations. The application of doxycycline might offer a new therapeutic approach to prevent NO-induced cochlea damage through ototoxic substances. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use.

PubMed

Kaneshiro, Bliss; Edelman, Alison; Carlson, Nichole E; Nichols, Mark; Forbes, Marci Messerle; Jensen, Jeffrey

2012-04-01

Unscheduled bleeding is the main side effect of continuous oral contraceptive pills (OCPs) and has been correlated with the up-regulation of matrix metalloprotineases (MMPs). The study objective was to determine if prophylactic administration of doxycycline (an MMP inhibitor at low subantimicrobial doses) would prevent unscheduled bleeding during the initiation of a continuous OCP. Subjects using cyclic hormonal contraceptives (combined OCPs, patch or ring) without unscheduled bleeding were switched to continuous OCPs (20 mcg ethinyl estradiol/100 mcg levonorgestrel). They were randomized to receive daily doxycycline [sustained-release subantimicrobial dose (40 mg daily)] or placebo for the first 84 days and then observed for an additional 28 days on the continuous OCP alone. The number of bleeding/spotting days and the time in days it took to achieve amenorrhea were compared using a t test. Sixty-five subjects were randomized. Although the use of doxycycline did not significantly decrease the number of mean bleeding/spotting days in the first 84 days of the study [doxycycline 14.75 (SE 2.30), placebo 17.78 (2.31), p=.36], women who received doxycycline had a significantly earlier onset of amenorrhea [mean last day of bleeding/spotting doxycycline 61.7 (7.7), placebo 85.2 (6.7), p=.03]. The coadministration of subantimicrobial-dose doxycycline during initiation of continuous OCPs results in a significant reduction in the length of time needed to achieve amenorrhea. Copyright © 2012 Elsevier Inc. All rights reserved.

A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use☆

PubMed Central

Kaneshiro, Bliss; Edelman, Alison; Carlson, Nichole E.; Nichols, Mark; Forbes, Marci Messerle; Jensen, Jeffrey

2016-01-01

Background Unscheduled bleeding is the main side effect of continuous oral contraceptive pills (OCPs) and has been correlated with the up-regulation of matrix metalloprotineases (MMPs). The study objective was to determine if prophylactic administration of doxycycline (an MMP inhibitor at low subantimicrobial doses) would prevent unscheduled bleeding during the initiation of a continuous OCP. Study Design Subjects using cyclic hormonal contraceptives (combined OCPs, patch or ring) without unscheduled bleeding were switched to continuous OCPs (20 mcg ethinyl estradiol/100 mcg levonorgestrel). They were randomized to receive daily doxycycline [sustained-release subantimicrobial dose (40 mg daily)] or placebo for the first 84 days and then observed for an additional 28 days on the continuous OCP alone. The number of bleeding/spotting days and the time in days it took to achieve amenorrhea were compared using a t test. Results Sixty-five subjects were randomized. Although the use of doxycycline did not significantly decrease the number of mean bleeding/spotting days in the first 84 days of the study [doxycycline 14.75 (SE 2.30), placebo 17.78 (2.31), p=.36], women who received doxycycline had a significantly earlier onset of amenorrhea [mean last day of bleeding/spotting doxycycline 61.7 (7.7), placebo 85.2 (6.7), p=.03]. Conclusion The coadministration of subantimicrobial-dose doxycycline during initiation of continuous OCPs results in a significant reduction in the length of time needed to achieve amenorrhea. PMID:22067758

A Novel and Rapid Method to Determine Doxycycline in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry

PubMed Central

Krishna, A. Chaitanya; Sathiyaraj, M.; Saravanan, R. S.; Chelladurai, R.; Vignesh, R.

2012-01-01

A simple, rapid, specific and sensitive liquid chromatography tandem mass spectrometric method has been developed and validated for the determination of doxycycline from the human plasma. Doxycycline is extracted from human plasma by solid phase extraction. Demeclocycline was used as an internal standard. Detection was performed at transitions of 444.800→428.200 for doxycycline and 464.700→448.100 for demeclocycline using mass spectrometry. Chromatographic separation of analyte and internal standard were carried out using a reverse phase C18, column at 0.500 ml/min flow. The assay of doxycycline is linear over the range of 0.055-7.612 μg/ml, with a precision <14.83%, regression coefficient (r2)=0.9961 and the limit of quantification in plasma for doxycycline was 0.055 μg/ml. Mean extraction recovery obtained was 95.55%. Samples are stable at room temperature for 6 h, processed samples were stable at least for 30.20 h and also stable at three freeze-thaw cycles. The method has been used to perform pharmacokinetic and bioequivalence studies in human plasma. PMID:23798780

Symmetrical Drug-related Intertriginous and Flexural Exanthema Induced by Doxycycline

PubMed Central

Thomas, Cristina; Weintraub, Gil S; Mostaghimi, Arash

2017-01-01

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug reaction characterized by erythema over the buttocks, thighs, groin, and flexural regions most commonly associated with the use of beta-lactam antibiotics. Although the exact pathophysiology of this disease remains unknown, it is theorized to be the result of a delayed hypersensitivity response presenting as a cutaneous eruption days to weeks after exposure to the drug. The treatment involves discontinuation of the suspected medication, symptomatic control of pruritus, and topical steroid therapy. A 51-year-old woman with homocystinuria and fibromyalgia was admitted with fevers, pancytopenia (later diagnosed to be acute myelogenous leukemia), and a targetoid cutaneous eruption in the setting of a recent tick bite. She was subsequently noted to have symmetric, pruritic, erythematous papules over the lateral neck, retroauricular regions, lateral aspects of the inframammary regions, medial upper arms, axillae, and the lower abdomen two weeks after starting doxycycline. Considering the morphology, distribution, and intense pruritis associated with the eruption, a diagnosis of SDRIFE was made. Doxycycline discontinuation along with topical steroid therapy resulted in the resolution of the eruption and pruritus. Given the widespread use of doxycycline, clinicians should be aware of this possible side effect. PMID:29340257

Treatment of unscheduled bleeding in continuous oral contraceptive users with doxycycline: a randomized controlled trial.

PubMed

Kaneshiro, Bliss; Edelman, Alison; Carlson, Nichole; Morgan, Kristin; Nichols, Mark; Jensen, Jeffrey

2010-06-01

To estimate whether doxycycline, a matrix metalloproteinase inhibitor, would decrease unscheduled bleeding associated with initiation of a continuous oral contraceptive pill. Participants initiating a continuous oral contraceptive pill (20 micrograms of ethinyl estradiol/90 micrograms of levonorgestrel) were randomly assigned to receive either doxycycline (100 mg orally twice daily) or placebo taken for 5 days at the onset of each bleeding or spotting episode during the first 84 days of the study period. For the final 28 days of the study, participants were observed on the oral contraceptive pill alone. The primary outcome was the number of bleeding and spotting days. A sample size of 66 (33 in each arm) was calculated to detect a 50% reduction in bleeding (beta=0.80, alpha=0.05) and accounted for a 30% dropout rate. Sixty-six women were randomly assinged (33 in each study group). There were no significant differences during the 84-day treatment in bleeding or spotting days (doxycycline [mean {standard error}, placebo, P=.32) or the length of the longest bleeding or spotting episode (doxycycline, placebo, P=.70) between study groups. Similarly, no significant differences in bleeding patterns existed between groups during the final 28 days. Doxycycline, administered once bleeding has started, does not decrease unscheduled bleeding or shorten episodes of unscheduled bleeding in continuous oral contraceptive pill users. I.

76 FR 72935 - Amended Authorization of Emergency Use of Doxycycline Hyclate Tablet Emergency Kits for Eligible...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-28

...] Amended Authorization of Emergency Use of Doxycycline Hyclate Tablet Emergency Kits for Eligible United... to the Emergency Use Authorization (EUA) (the Authorization) for doxycycline hyclate tablet emergency... Doxycyline Hyclate Tablet Emergency Kits, as Amended In 2004, the Secretary of the Department of Homeland...

Doxycycline Compliance at Bagram Air Field

DTIC Science & Technology

2014-05-01

doxycycline absorption. In 2008, the Institute of Medicine issued a report entitled ·’Use of Dietary Supplements by Military Personnel" that reported 34...absorption by tetracycline. Br J Clin Pharmacal. 1975 February; 2(1): 94- 96. 19. 0. M. e. Greenwood MRC, "Use of Dietary Supplements by Military...Personnel.Institute of Medicine (US) Committee on Dietary Supplement Use by Military Personnel," National Academies Press, Washington (DC), 2008. 20

Photocatalytic removal of doxycycline from aqueous solution using ZnO nano-particles: a comparison between UV-C and visible light.

PubMed

Pourmoslemi, Shabnam; Mohammadi, Ali; Kobarfard, Farzad; Amini, Mohsen

2016-10-01

Zinc oxide nano-particles were synthesized, characterized and used for photocatalytic degradation of doxycycline using UV-C and visible light. Effects of several operational factors including initial pH of antibiotic solution, initial antibiotic concentration and ZnO nano-particles loading amount were investigated. Comparing photocatalytic degradation and mineralization of doxycycline under UV-C and visible light showed successful application of the method under both light sources. However, reaction rate was higher under UV-C irradiation, which degraded doxycycline almost completely in 5 hours, and 68% mineralization was achieved. Synthesized ZnO nano-particles were successfully applied for photocatalytic degradation of doxycycline in a pharmaceutical wastewater sample. The process was fitted to the pseudo first order kinetic model with rate constants in the range of 6-22(×10 -3 ) mg L -1 min -1 with respect to initial concentration of doxycycline under UV-C irradiation. The Langmuir-Hinshelwood model was also employed for describing the photocatalytic reaction with surface reaction kinetic constant k c and equilibrium adsorption constant K LH values calculated as 0.12 mg L -1 min -1 and 2.2 L mg -1 , respectively. Degradation of doxycycline was followed by UV-visible spectroscopy and a validated stability indicating high-performance liquid chromatography method that was developed using stressed samples of doxycycline and could selectively determine doxycycline in the presence of its degradation products. Mass spectrometry was used for determining final degradation products.

Comparing azithromycin and doxycycline for the treatment of rectal chlamydial infection: a retrospective cohort study

PubMed Central

Khosropour, Christine M.; Dombrowski, Julia C.; Barbee, Lindley A.; Manhart, Lisa E.; Golden, Matthew R.

2015-01-01

Background Centers for Disease Control and Prevention (CDC) guidelines recommend azithromycin or doxycycline for treatment of rectal chlamydial infection. Methods We created a retrospective cohort of male patients diagnosed with rectal chlamydia 1993-2012 at a sexually transmitted disease clinic in Seattle, Washington. Men were included in the analysis if they were treated with azithromycin (1g single dose) or doxycycline (100mg BID x 7 days) within 60 days of chlamydia diagnosis and returned for repeat testing 14-180 days post-treatment. We compared the risk of persistent/recurrent rectal chlamydial infection among recipients of the two drug regimens using four follow-up testing time intervals (14 to 30, 60, 90, and 180 days). Results Of 1,835 cases of rectal chlamydia diagnosed in the study period, 1,480 (81%) were treated with azithromycin or doxycycline without a second drug active against C. trachomatis. Of these, 407 (33%) of 1231 azithromycin-treated men and 95 (38%) of 249 doxycycline-treated men were re-tested 14-180 days after treatment (P=0.12); 88 (22%) and 8 (8%), respectively, had persistent/recurrent infection (P=0.002). Persistent/recurrent infection was higher among men treated with azithromycin compared to doxycycline at 14-30 days (4/53 (8%) vs. 0/20 (0%)), 14-60 days (23/136 (17%) vs. 0/36 (0%)), and 14-90 days (50/230 (22%) vs. 2/56 (4%)). In multivariate analysis, azithromycin-treated men had a significantly higher risk of persistent/recurrent infection in the 14-90 days (aRR=5.2, 95% CI=1.3-21.0) and 14-180 days (aRR=2.4, 95% CI=1.2-4.8) after treatment. Conclusions These data suggest that doxycycline may be more effective than azithromycin in the treatment of rectal chlamydial infections. PMID:24413484

Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis--A randomised placebo-controlled pilot trial.

PubMed

Nukarinen, Eija; Tervahartiala, Taina; Valkonen, Miia; Hynninen, Marja; Kolho, Elina; Pettilä, Ville; Sorsa, Timo; Backman, Janne; Hästbacka, Johanna

2015-09-01

An overwhelming inflammatory process is the hallmark of severe sepsis and septic shock. Matrix metalloproteinases (MMPs)-8 and -9 are released from neutrophils and activated in sepsis to participate in inflammation in several ways. High levels of MMP-8 may associate with increased ICU mortality. The activity of MMP-8 and -9 is regulated by a natural inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Moreover, MMPs are chemically inhibited by tetracycline-group antibiotics, such as doxycycline. We therefore aimed to study plasma concentration and MMP inhibition after intravenous doxycycline in critically ill patients with severe sepsis and septic shock in a prospective, randomised, placebo-controlled double-blinded pilot trial. Twenty-four patients with severe sepsis or septic shock were randomised in 3 groups. Group 1 received 200, 100 and 100mg, group 2 100, 50 and 50mg of intravenous doxycycline and group 3 placebo on three consecutive days. We measured doxycycline concentrations from baseline up to day 5. MMPs and TIMP-1 concentrations were measured from baseline up to day 10 of study and we compared their changes over time from baseline to 72 h and from baseline to 120 h. Data from 23 patients were analysed. At 72 h all patients in group 1 showed doxycycline concentrations >1 mg/l, whereas none in group 2 did. No serious adverse effects of the drug were recorded. We observed no differences over time up to 72 or up to 120 h in the concentrations or activities of MMP-8, -9 or TIMP-1 in any of the groups. We found intravenous doxycycline 100, 50 and 50mg to be adequate to achieve a sub-antimicrobial concentration in patients with severe sepsis or septic shock but having no impact on MMP-8, -9 or TIMP-1 concentrations or activities. Copyright © 2015 Elsevier Ltd. All rights reserved.

Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy

PubMed Central

Lamb, Rebecca; Fiorillo, Marco; Chadwick, Amy; Ozsvari, Bela; Reeves, Kimberly J.; Smith, Duncan L.; Clarke, Robert B.; Howell, Sacha J.; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Peiris-Pagès, Maria; Sotgia, Federica; Lisanti, Michael P.

2015-01-01

DNA-PK is an enzyme that is required for proper DNA-repair and is thought to confer radio-resistance in cancer cells. As a consequence, it is a high-profile validated target for new pharmaceutical development. However, no FDA-approved DNA-PK inhibitors have emerged, despite many years of drug discovery and lead optimization. This is largely because existing DNA-PK inhibitors suffer from poor pharmacokinetics. They are not well absorbed and/or are unstable, with a short plasma half-life. Here, we identified the first FDA-approved DNA-PK inhibitor by “chemical proteomics”. In an effort to understand how doxycycline targets cancer stem-like cells (CSCs), we serendipitously discovered that doxycycline reduces DNA-PK protein expression by nearly 15-fold (> 90%). In accordance with these observations, we show that doxycycline functionally radio-sensitizes breast CSCs, by up to 4.5-fold. Moreover, we demonstrate that DNA-PK is highly over-expressed in both MCF7- and T47D-derived mammospheres. Interestingly, genetic or pharmacological inhibition of DNA-PK in MCF7 cells is sufficient to functionally block mammosphere formation. Thus, it appears that active DNA-repair is required for the clonal expansion of CSCs. Mechanistically, doxycycline treatment dramatically reduced the oxidative mitochondrial capacity and the glycolytic activity of cancer cells, consistent with previous studies linking DNA-PK expression to the proper maintenance of mitochondrial DNA integrity and copy number. Using a luciferase-based assay, we observed that doxycycline treatment quantitatively reduces the anti-oxidant response (NRF1/2) and effectively blocks signaling along multiple independent pathways normally associated with stem cells, including STAT1/3, Sonic Hedgehog (Shh), Notch, WNT and TGF-beta signaling. In conclusion, we propose that the efficacy of doxycycline as a DNA-PK inhibitor should be tested in Phase-II clinical trials, in combination with radio-therapy. Doxycycline has

Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tewari-Singh, Neera, E-mail: Neera.Tewari-Singh@ucdenver.edu; Jain, Anil K., E-mail: Anil.Jain@ucdenver.edu; Inturi, Swetha, E-mail: Swetha.Inturi@ucdenver.edu

There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and everymore » 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost

Higher bioavailability of doxycycline in broiler chickens with a novel in-feed pharmaceutical formulation.

PubMed

Gutiérrez, Lilia; Zermeño, Juan; Alcalá, Yazmín; Sumano, Héctor

2017-08-01

Bioavailability of a new, long-acting (LA) pharmaceutical preparation for administering doxycycline as in-feed medication to broiler chickens was compared to the standard in-feed administration of doxycycline. A commercial poultry house harboring Ross-308 broiler chickens, weighing 450 g, was divided into 7 sections as follows: doxy-FOLA group (n = 6,000 chickens divided into 3 replicates) medicated with 10% doxycyline, long-acting pellets at a dose of 400 g of doxycycline HCl/ton of food, resulting in a calculated dose of 48 mg/kg for 5 d; doxy-ref group (n = 6,000, divided into 3 replicates) medicated as for doxy-FOLA, but using a 20% commercial preparation of doxycycline. A third group of 300 broiler chickens (divided into 3 replicates), received a single IV dose of 48 mg/kg from a 2.4% solution of doxycycline HCl under ketamine anesthesia. Blood samples were obtained at designated times, serum was harvested, and doxycycline concentrations determined by high-performance liquid chromatography (HPLC). Bioavailability values were 156% and 227% on d 1 and 5 for doxy-FOLA and 13% and 23% for doxy-ref, on the same days. Mean residence time (MRT) and elimination half-life (T½β) were statistically different (P < 0.05) in doxy-FOLA group as compared to doxy-ref group (MRT: 26 h and 5.2 h; and T½β: 18 h vs 3 h, on the first day for doxy-FOLA and doxy-ref, respectively). Based on 3 levels of bacterial sensitivity of E. coli derived from a small survey carried out (i.e., 1.0, 2.0, and 4.0 μg/mL) and considering pharmacokinetic/pharmacodynamic (PK/PD) ratios required for this time-dependent antibacterial drug, it is possible to postulate that doxy-FOLA outstrips the reference preparation maintaining higher and more prolonged serum concentrations of doxycycline and consequently complying better with PK/PD ratios regarded as optimal for this drug. The advantages of using doxy-FOLA in poultry medicine include a more comprehensive use of the active principle

Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility

PubMed Central

Collins, Alexander; Faraji, Farshid; Wang, Guanying; Aguayo, Esteban; Ge, Liang; Saloner, David; Wallace, Arthur W.; Baker, Anthony J.; Lovett, David H.

2018-01-01

Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI). Antero-apical MI was created in 14 sheep. Seven sheep received doxycycline 0.8 mg/kg/hr IV for two weeks. Cardiac MRI was performed two weeks before, and then two and six weeks after MI. Two sheep died prior to MRI at six weeks from surgical/anesthesia-related causes. The remaining 12 sheep completed the protocol. Doxycycline induced a sustained reduction in intracellular MMP-2 by Western blot (3649±643 MI+Dox vs 9236±114 MI relative intensity; p = 0.0009), an improvement in ex-vivo contractility (65.3±2.0 MI+Dox vs 39.7±0.8 MI mN/mm2; p<0.0001) and an increase in ventricular wall thickness at end-systole 1.0 cm from the infarct edge (12.4±0.6 MI+Dox vs 10.0±0.5 MI mm; p = 0.0095). Administration of doxycycline for a limited two week period is associated with a sustained improvement in ex-vivo contractility and an increase in wall thickness at end-systole in the border zone six weeks after MI. These findings were associated with a reduction in intracellular MMP-2 activity. PMID:29432443

Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility.

PubMed

Spaulding, Kimberly; Takaba, Kiyoaki; Collins, Alexander; Faraji, Farshid; Wang, Guanying; Aguayo, Esteban; Ge, Liang; Saloner, David; Wallace, Arthur W; Baker, Anthony J; Lovett, David H; Ratcliffe, Mark B

2018-01-01

Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI). Antero-apical MI was created in 14 sheep. Seven sheep received doxycycline 0.8 mg/kg/hr IV for two weeks. Cardiac MRI was performed two weeks before, and then two and six weeks after MI. Two sheep died prior to MRI at six weeks from surgical/anesthesia-related causes. The remaining 12 sheep completed the protocol. Doxycycline induced a sustained reduction in intracellular MMP-2 by Western blot (3649±643 MI+Dox vs 9236±114 MI relative intensity; p = 0.0009), an improvement in ex-vivo contractility (65.3±2.0 MI+Dox vs 39.7±0.8 MI mN/mm2; p<0.0001) and an increase in ventricular wall thickness at end-systole 1.0 cm from the infarct edge (12.4±0.6 MI+Dox vs 10.0±0.5 MI mm; p = 0.0095). Administration of doxycycline for a limited two week period is associated with a sustained improvement in ex-vivo contractility and an increase in wall thickness at end-systole in the border zone six weeks after MI. These findings were associated with a reduction in intracellular MMP-2 activity.

Antimicrobial synergy between carprofen and doxycycline against methicillin-resistant Staphylococcus pseudintermedius ST71.

PubMed

Brochmann, Rikke Prejh; Helmfrid, Alexandra; Jana, Bimal; Magnowska, Zofia; Guardabassi, Luca

2016-06-24

New therapeutic strategies are needed to face the rapid spread of multidrug-resistant staphylococci in veterinary medicine. The objective of this study was to identify synergies between antimicrobial and non-antimicrobial drugs commonly used in companion animals as a possible strategy to restore antimicrobial susceptibility in methicillin-resistant Staphylococcus pseudintermedius (MRSP). A total of 216 antimicrobial/non-antimicrobial drug combinations were screened by disk diffusion using a clinical MRSP sequence type (ST) 71 strain resistant to all six antimicrobials tested (ampicillin, ciprofloxacin, clindamycin, doxycycline, oxacillin and trimethoprim/sulfamethoxazole). The most promising drug combination (doxycycline-carprofen) was further assessed by checkerboard testing extended to four additional MRSP strains belonging to ST71 or ST68, and by growth inhibition experiments. Seven non-antimicrobial drugs (bromhexine, acepromazine, amitriptyline, clomipramine, carprofen, fluoxetine and ketoconazole) displayed minimum inhibitory concentrations (MICs) ranging between 32 and >4096 mg/L, and enhanced antimicrobial activity of one or more antimicrobials. Secondary screening by checkerboard assay revealed a synergistic antimicrobial effect between carprofen and doxycycline, with the sum of the fractional inhibitory concentration indexes (ΣFICI) ranging between 0.3 and 0.5 depending on drug concentration. Checkerboard testing of multiple MRSP strains revealed a clear association between synergy and carriage of tetK, which is a typical feature of MRSP ST71. An increased growth inhibition was observed when MRSP ST71 cells in exponential phase were exposed to 0.5/32 mg/L of doxycycline/carprofen compared to individual drug exposure. Carprofen restores in vitro susceptibility to doxycycline in S. pseudintermedius strains carrying tetK such as MRSP ST71. Further research is warranted to elucidate the molecular mechanism behind the identified synergy and its linkage to

Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study.

PubMed

Foulks, Gary N; Borchman, Douglas; Yappert, Marta; Kakar, Shelley

2013-01-01

Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal. Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels

Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection.

PubMed

White, Cassandra R; Jodlowski, Tomasz Z; Atkins, Dylan T; Holland, Nicole G

2017-08-01

To report on a patient with a symptomatic, polymicrobial Escherichia coli and multidrug-resistant (MDR), extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae urinary tract infection (UTI) who was successfully treated with oral doxycycline hyclate. A 70-year-old white male inpatient with a history of recurrent UTI, type 2 diabetes, hypertension, obesity, and diverticular disease was diagnosed with UTI and empirically treated with oral ciprofloxacin. Symptoms persisted 2 days later, and the patient was transitioned to amoxicillin/clavulanate by a different provider. The next day, upon receipt of the urine culture and susceptibility panel revealing E coli and MDR, ESBL-positive K pneumoniae infection, treatment was switched to doxycycline hyclate, which resulted in clinical improvement. Complicated UTI involving multiple pathogens requires careful clinical judgment to select the appropriate antimicrobial agent, improve clinical outcomes, and prevent resistance. Treatment with doxycycline was based on the susceptibility panel and local resistance patterns. Advantages of doxycycline for UTI include its oral formulation, wide spectrum of activity, ability to achieve high concentration in the urine, and low toxicity. Doxycycline hyclate may be an effective treatment option for patients with susceptible MDR UTI.

Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells.

PubMed

Ogut, Deniz; Reel, Buket; Gonen Korkmaz, Ceren; Arun, Mehmet Zuhuri; Cilaker Micili, Serap; Ergur, Bekir Ugur

2016-01-01

Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-κB) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-κB signaling. PC3 cells were incubated with LPS (0.5 μg/mL) for 24 h in the presence or absence of doxycycline (5 μg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP-10, NF-κB/p65, IκB-α, p-IκB-α, IKK-β were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-κB /p65, p-IκB-α, IKK-β and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and IκB-α was affected by neither LPS nor doxycycline. Our findings indicate that doxycycline inhibits the expression of various MMPs and NF-κB signaling may play a role in the regulation of MMPs expression in LPS-induced PC3 human prostate cancer cells.

Efficacy of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg versus metronidazole gel 1% plus oral doxycycline 40 mg in mild-to-moderate papulopustular rosacea.

PubMed

Del Rosso, James Q; Bruce, Suzanne; Jarratt, Michael; Menter, Alan; Staedtler, Gerald

2010-06-01

Rosacea is a leading reason why people seek the care of a dermatologist, accounting for nearly 7 million office visits annually. Pharmacologic treatments include both topical and oral medications, which are increasingly being used in combination, especially at the outset of therapy. This exploratory study assesses the safety, effectiveness and speed of onset of two common topical agents for the treatment of rosacea--azelaic acid gel (AzA) 15% and metronidazole gel 1%--used in conjunction with anti-inflammatory dose doxycycline (40 mg once daily). Men and women (n = 207) with mild-to-moderate papulopustular rosacea were enrolled and randomized to receive either AzA gel 15% twice daily plus doxycycline 40 mg once daily (AzA group) or metronidazole gel 1% once daily plus doxycycline 40 mg once daily (Metro group) for 12 weeks. Both regimens were safe, efficacious and well tolerated. Efficacy parameters revealed a possible trend toward greater and earlier benefit with the AzA-based regimen than with the metronidazole-based regimen. These findings warrant further investigation in a sufficiently powered study.

Sealing ability of mineral trioxide aggregate (MTA) combined with distilled water, chlorhexidine, and doxycycline.

PubMed

Arruda, Roberta A A; Cunha, Rodrigo S; Miguita, Kenner B; Silveira, Cláudia F M; De Martin, Alexandre S; Pinheiro, Sérgio L; Rocha, Daniel G P; Bueno, Carlos E S

2012-09-01

The aim of this study was to evaluate the sealing ability of mineral trioxide aggregate (MTA Bio) combined with different mixing agents (distilled water, chlorhexidine, doxycycline), used as an apical root-end filling material. Forty-two extracted human teeth were divided into three groups (n = 12); six teeth were used as controls. Root-ends were resected at 90 degrees, 3 mm from the apex. Root-end cavities were prepared using ultrasonic tips and filled with MTA Bio plus distilled water, 2% chlorhexidine solution, or 10% doxycycline solution. Apical sealing was assessed by microleakage of 50% silver nitrate solution. Roots were longitudinally sectioned in a buccolingual plane and analyzed using an operating microscope (20× magnification). Depth of dye leakage into the dentinal walls was measured in millimeters. Results were analyzed using ANOVA and Tukey's test (P = 0.05). MTA Bio plus distilled water showed significantly higher mean leakage results (1.06 mm) when compared with MTA Bio plus doxycycline (0.61 mm), and higher, although not significant, results when compared with MTA Bio plus chlorhexidine (0.79 mm). In conclusion, replacing distilled water with two biologically active mixing agents (doxycycline and chlorhexidine) did not alter the sealing properties of MTABio. The antimicrobial properties of these combinations should be further investigated.

Efficacy of Doxycycline, Azithromycin, or Trovafloxacin for Treatment of Experimental Rocky Mountain Spotted Fever in Dogs

PubMed Central

Breitschwerdt, E. B.; Papich, M. G.; Hegarty, B. C.; Gilger, B.; Hancock, S. I.; Davidson, M. G.

1999-01-01

Dogs were experimentally inoculated with Rickettsia rickettsii (canine origin) in order to compare the efficacies of azithromycin and trovafloxacin to that of the current antibiotic standard, doxycycline, for the treatment of Rocky Mountain spotted fever. Clinicopathologic parameters, isolation of rickettsiae in tissue culture, and PCR amplification of rickettsial DNA were used to evaluate the response to therapy or duration of illness (untreated infection control group) in the four groups. Concentrations of the three antibiotics in plasma and blood cells were measured by high-performance liquid chromatography. Doxycycline and trovafloxacin treatments resulted in more-rapid defervescence, whereas all three antibiotics caused rapid improvement in attitudinal scores, blood platelet numbers, and the albumin/total-protein ratio. Based upon detection of retinal vascular lesions by fluorescein angiography, trovafloxacin and doxycycline substantially decreased rickettsia-induced vascular injury to the eye, whereas the number of ocular lesions in the azithromycin group did not differ from that in the infection control group. As assessed by tissue culture isolation, doxycycline resulted in the earliest apparent clearance of viable circulating rickettsiae; however, rickettsial DNA could still be detected in the blood of some dogs from all four groups on day 21 postinfection, despite our inability to isolate viable rickettsiae at that point. As administered in this study, trovafloxacin was as efficacious as doxycycline but azithromycin proved less efficacious, possibly due to the short duration of administration. PMID:10103185

Genetic diversity of Streptococcus equi subsp. zooepidemicus and doxycycline resistance in kennelled dogs.

PubMed

Chalker, Victoria J; Waller, Andrew; Webb, Katy; Spearing, Emma; Crosse, Patricia; Brownlie, Joe; Erles, Kerstin

2012-06-01

The genetic diversity and antibiotic resistance profiles of 38 Streptococcus equi subsp. zooepidemicus isolates were determined from a kennelled canine population during two outbreaks of hemorrhagic pneumonia (1999 to 2002 and 2007 to 2010). Analysis of the szp gene hypervariable region and the 16S-23S rRNA intergenic spacer region and multilocus sequence typing (MLST) indicated a predominant tetO-positive, doxycycline-resistant ST-10 strain during 1999 to 2002 and a predominant tetM-positive doxycycline-resistant ST-62 strain during 2007 to 2010.

Doxycycline protects human intestinal cells from hypoxia/reoxygenation injury: Implications from an in-vitro hypoxia model.

PubMed

Hummitzsch, Lars; Zitta, Karina; Berndt, Rouven; Kott, Matthias; Schildhauer, Christin; Parczany, Kerstin; Steinfath, Markus; Albrecht, Martin

2017-04-15

Intestinal ischemia/reperfusion (I/R) injury is a grave clinical emergency and associated with high morbidity and mortality rates. Based on the complex underlying mechanisms, a multimodal pharmacological approach seems necessary to prevent intestinal I/R injury. The antibiotic drug doxycycline, which exhibits a wide range of pleiotropic therapeutic properties, might be a promising candidate for also reducing I/R injury in the intestine. To investigate possible protective effects of doxycycline on intestinal I/R injury, human intestinal CaCo-2 cells were exposed to doxycycline at clinically relevant concentrations. In order to mimic I/R injury, CaCo-2 were thereafter subjected to hypoxia/reoxygenation by using our recently described two-enzyme in-vitro hypoxia model. Investigations of cell morphology, cell damage, apoptosis and hydrogen peroxide formation were performed 24h after the hypoxic insult. Hypoxia/reoxygenation injury resulted in morphological signs of cell damage, elevated LDH concentrations in the respective culture media (P<0.001) and increased protein expression of proapoptotic caspase-3 (P<0.05) in the intestinal cultures. These events were associated with increased levels hydrogen peroxide (P<0.001). Preincubation of CaCo-2 cells with different concentrations of doxycycline (5µM, 10µM, 50µM) reduced the hypoxia induced signs of cell damage and LDH release (P<0.001 for all concentrations). The reduction of cellular damage was associated with a reduced expression of caspase-3 (5µM, P<0.01; 10µM, P<0.01; 50µM, P<0.05), while hydrogen peroxide levels remained unchanged. In summary, doxycycline protects human intestinal cells from hypoxia/reoxygenation injury in-vitro. Further animal and clinical studies are required to prove the protective potential of doxycycline on intestinal I/R injury under in-vivo conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of radiotherapy, adhesive systems and doxycycline on the bond strength of the dentin-composite interface.

PubMed

Freitas Soares, Eveline; Zago Naves, Lucas; Bertolazzo Correr, Américo; Costa, Ana Rosa; Consani, Simonides; Soares, Carlos José; Garcia-Godoy, Franklin; Correr-Sobrinho, Lourenço

2016-12-01

To investigate the effect of radiotherapy, doxycycline and adhesive systems on the microtensile bond strength (μTBS) of the dentin-composite interface. 60 human third molars were sectioned to expose middle dentin surface and distributed according to: (1) adhesive system (Adper Scotchbond MP and Clearfil SE Bond) applied, (2) application or not of doxycycline, and (3) submission to 60 Gy total radiation (2 Gy daily doses, 5 days/week for 6 weeks) before restoration procedure (RtRes); after restoration procedure (ResRt) or not submitted to radiotherapy (Control group). Specimens were tested for μTBS and mode of failure were evaluated under optical microscopy. The bonding interface was evaluated with a scanning electron microscope (SEM). Data was submitted to three-way ANOVA and Tukey's test (α= 0.05). There was no significant difference between the μTBS (MPa) of Adper Scotchbond MP (25.5±11.1) and Clearfil SE (27.6±9.1). Control (30.5±10.9) and ResRt (29.2±10.4) presented μTBS significantly higher than RtRes (23.1±7.2). Doxycycline (21.7±7.6) significantly reduced μTBS compared to groups without doxycycline application (33.6±8.6). Dentin cohesive failure mode was predominant for RtRes and mixed failure mode for ResRt. Mixed and adhesive failures were frequently observed in control groups. SEM showed adhesive penetration in dentin tubules in all groups, regardless of the radiotherapy and the application of doxycycline. The radiotherapy before composite restoration procedure decreased the μTBS. No statistical difference was observed between the adhesive systems. The doxycycline reduced μTBS regardless of the other conditions. Composite restoration procedure should be done before radiotherapy, regardless of the adhesive system used.

Inhibition of extracellular matrix production and remodeling by doxycycline in smooth muscle cells.

PubMed

Palomino-Morales, Rogelio; Torres, Carolina; Perales, Sonia; Linares, Ana; Alejandre, Maria Jose

2016-12-01

Alterations in the extracellular matrix (ECM) production and remodeling of smooth muscle cells (SMCs) have been implicated in processes related to the differentiation in atherosclerosis. Due to the anti-atherosclerotic properties of the tetracyclines, we aimed to investigate whether cholesterol supplementation changes the effect of doxycycline over the ECM proteins synthesis and whether isoprenylated proteins and Rho A protein activation are affected. SMC primary culture isolated from chicks exposed to atherogenic factors in vivo (a cholesterol-rich diet, SMC-Ch), comparing it with control cultures isolated after a standard diet (SMC-C). After treatment with 20 nM doxycycline, [H 3 ]-proline and [H 3 ]-mevalonate incorporation were used to measure the synthesis of collagen and isoprenylated proteins, respectively. Real-time PCR was assessed to determine col1a2, col2a1, col3a1, fibronectin, and mmp2 gene expression and the pull-down technique was applied to determine the Rho A activation state. A higher synthesis of collagens and isoprenylated proteins in SMC-Ch than in SMC-C was determined showing that doxycycline inhibits ECM production and remodeling in both SMC types of cultures. Moreover, preliminary results about the effect of doxycycline on protein isoprenylation and Rho A protein activation led us to discuss the possibility that membrane G-protein activation pathways could mediate the molecular mechanism. Copyright © 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania.

PubMed

Mwengee, William; Butler, Thomas; Mgema, Samuel; Mhina, George; Almasi, Yusuf; Bradley, Charles; Formanik, James B; Rochester, C George

2006-03-01

Over the past 50 years, antibiotics of choice for treatment of plague, including streptomycin, chloramphenicol, and tetracycline, have mostly become outdated or unavailable. To test gentamicin in the treatment of naturally occurring plague and the implications of its use in the treatment of bioterrorist plague, a randomized, comparative, open-label, clinical trial comparing monotherapy with gentamicin or doxycycline was conducted in Tanzania. Sixty-five adults and children with symptoms of bubonic, septicemic, or pneumonic plague of < or =3 days duration were enrolled in the study. Bubo aspirates and blood were cultured for Yersinia pestis. Acute-phase and convalescent-phase serum samples were tested for antibody against fraction 1 antigen of Y. pestis. Thirty-five patients were randomized to receive gentamicin (2.5 mg/kg intramuscularly every 12 h for 7 days), and 30 patients were randomized to receive doxycycline (100 mg [adults] and 2.2 mg/kg [children] orally every 12 h for 7 days). Serum creatinine concentrations were measured before and after treatment, and peak and trough concentrations of antibiotics were measured. Three patients, 2 of whom were treated with gentamicin and 1 of whom was treated with doxycycline, died on the first or second day of treatment, and these deaths were attributed to advanced disease and complications including pneumonia, septicemia, hemorrhage, and renal failure at the start of therapy. All other patients experienced cure or an improved condition after receiving therapy, resulting in favorable response rates of 94% for gentamicin (95% CI, 81.1%-99.0%) and 97% for doxycycline (95% CI, 83.4%-99.8%). Y. pestis isolates obtained from 30 patients belonged to biotype antigua and were susceptible to gentamicin and doxycycline, which had MICs of 0.13 mg/L and 0.25-0.5 mg/L, respectively. Serum concentrations of antibiotics were within therapeutic ranges, and adverse events were infrequent. Patients treated with gentamicin demonstrated a

A novel flow injection spectrophotometric method using plant extracts as green reagent for the determination of doxycycline

NASA Astrophysics Data System (ADS)

Palamy, Sysay; Ruengsitagoon, Wirat

2017-01-01

A novel flow injection spectrophotometric method was developed for the determination of doxycycline in pharmaceutical preparations using iron(III) contained in extracts from plants. The assay was based on the complex formed between doxycycline and iron(III) characterized by an absorption maximum at 435 nm. The calibration graphs obtained over the doxycycline concentration range 5-250 μg mL- 1 gave correlation coefficients of 0.9979, 0.9987 and 0.9987 with the three green reagents prepared from Senna alata (L.) Roxb. (S. alata), Polygonum hydropiper L. (P. hydropiper) or Diplazium esculentum (Retz.) Sw. (D. esculentum), respectively. The relative standard deviations of the repeatability was < 2.00%. The percentage recoveries were in the range of 98.27-101.03%. Doxycycline contents obtained by this new method and by the reference methods reported in literature were in agreement at 95% confidence level with the paired t-test. The sample throughput was 36 h- 1 for each green reagent.

Genetic Diversity of Streptococcus equi subsp. zooepidemicus and Doxycycline Resistance in Kennelled Dogs

PubMed Central

Chalker, Victoria J.; Waller, Andrew; Webb, Katy; Spearing, Emma; Crosse, Patricia; Brownlie, Joe

2012-01-01

The genetic diversity and antibiotic resistance profiles of 38 Streptococcus equi subsp. zooepidemicus isolates were determined from a kennelled canine population during two outbreaks of hemorrhagic pneumonia (1999 to 2002 and 2007 to 2010). Analysis of the szp gene hypervariable region and the 16S-23S rRNA intergenic spacer region and multilocus sequence typing (MLST) indicated a predominant tetO-positive, doxycycline-resistant ST-10 strain during 1999 to 2002 and a predominant tetM-positive doxycycline-resistant ST-62 strain during 2007 to 2010. PMID:22495558

Comparative trial of rifampin-doxycycline versus tetracycline-streptomycin in the therapy of human brucellosis.

PubMed Central

Ariza, J; Gudiol, F; Pallarés, R; Rufí, G; Fernández-Viladrich, P

1985-01-01

In an attempt to compare the efficacy of rifampin-doxycycline with tetracycline-streptomycin for the treatment of human brucellosis, we administered both combinations for a 30-day period, similar to the period recommended by the World Health Organization in a prospective, randomized trial. Forty-six patients were included in the final study (36 men and 10 women); 41 had blood cultures positive for Brucella melitensis. The 28 patients in group A received tetracycline hydrochloride at doses of 0.5 g every 6 h or doxycycline at 100 mg every 12 h for 30 days plus 1 g of streptomycin a day for 21 days. The 18 patients in group B received rifampin at 15 mg/kg per day in a single morning dose plus 100 mg of doxycycline every 12 h for 30 days. For patients with focal disease from both groups, therapy was prolonged to 45 days. All patients underwent rigorous clinical and bacteriological long-term follow-up. There were no therapeutic failures in either group, and the defervescence period was similar for both groups (3.1 days for group A, 2.6 days for group B). Two patients (7.1%) from group A had relapses, as did seven (38.8%) from group B (P = 0.024), and blood cultures again became positive for B. melitensis in all of them. In both groups treatment was generally well tolerated. The results strongly suggest that the rifampin-doxycycline combination is a less efficacious mode of therapy for brucellosis to prevent relapses than is the classical tetracycline-streptomycin combination when both are administered for 30 days. A more prolonged period of administration of the rifampin-doxycycline combination may be required to obtain the same low relapse rate as that achieved with the classical tetracycline-streptomycin treatment. PMID:4073878

Doxycycline Inhibits Polarization of Macrophages to the Proangiogenic M2-type and Subsequent Neovascularization*

PubMed Central

He, Lizhi; Marneros, Alexander G.

2014-01-01

Macrophages occur along a continuum of functional states between M1-type polarized macrophages with antiangiogenic and antitumor activity and M2-type polarized macrophages, which have been implicated to promote angiogenesis and tumor growth. Proangiogenic M2-type macrophages promote various pathologic conditions, including choroidal neovascularization in models of neovascular age-related macular degeneration, or certain cancers, such as glioblastoma multiforme. Thus, a potential novel therapeutic approach to target pathological angiogenesis in these conditions would be to inhibit the polarization of macrophages toward the proangiogenic M2-type. However, no pharmacological inhibitors of M2-type macrophage polarization have been identified yet. Here we performed an unbiased pharmacological and small chemical screen to identify drugs that inhibit proangiogenic M2-type macrophage polarization and block pathologic macrophage-driven neovascularization. We identified the well tolerated and commonly used antibiotic doxycycline as a potent inhibitor of M2-type polarization of macrophages. Doxycycline inhibited, in a dose-dependent manner, M2-type polarization of human and bone marrow-derived mouse macrophages without affecting cell viability. Furthermore, doxycycline inhibited M2-type macrophage polarization and subsequent neovascularization in vivo in a laser injury model of choroidal neovascularization. Thus, doxycycline could be used to enhance current antiangiogenic treatment approaches in various conditions that are promoted by proangiogenic M2-type macrophages, including neovascular age-related macular degeneration and certain cancers. PMID:24505138

Improved clinical outcome and biomarkers in adults with papulopustular rosacea treated with doxycycline modified-release capsules in a randomized trial.

PubMed

Di Nardo, Anna; Holmes, Anna D; Muto, Yumiko; Huang, Eugene Y; Preston, Norman; Winkelman, Warren J; Gallo, Richard L

2016-06-01

Patients with rosacea have increased amounts of cathelicidin and protease activity but their usefulness as disease biomarkers is unclear. We sought to evaluate the effect of doxycycline treatment on cathelicidin expression, protease activity, and clinical response in rosacea. In all, 170 adults with papulopustular rosacea were treated for 12 weeks with doxycycline 40-mg modified-release capsules or placebo in a multicenter, randomized, double-blind, placebo-controlled study. Clinical response was compared with cathelicidin and protease activity in stratum corneum samples obtained by tape strip and in skin biopsy specimens obtained from a random subset of patients. Treatment with doxycycline significantly reduced inflammatory lesions and improved investigator global assessment scores compared with placebo. Cathelicidin expression and protein levels decreased over the course of 12 weeks in patients treated with doxycycline. Low levels of protease activity and cathelicidin expression at 12 weeks correlated with treatment success. Low protease activity at baseline was a predictor of clinical response in the doxycycline treatment group. Healthy control subjects were not studied. Improved clinical outcome correlated with reduced cathelicidin and protease activity, supporting both the mechanism of doxycycline and the potential of these molecules as biomarkers for rosacea. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Evaluation of drug content (potency) for compounded and FDA-approved formulations of doxycycline on receipt and after 21 days of storage.

PubMed

KuKanich, Kate; KuKanich, Butch; Slead, Tanner; Warner, Matt

2017-10-01

OBJECTIVE To determine drug content (potency) of compounded doxycycline formulations for veterinary use and of US FDA-approved doxycycline formulations for human use < 24 hours after receipt (day 1) and after 21 days of storage under recommended conditions (day 21). DESIGN Evaluation study. SAMPLE FDA-approved doxycycline tablets (100 mg), capsules (100 mg), and liquid suspension (10 mg/mL) and compounded doxycycline formulations from 3 pharmacies (tablets [25, 100, and 150 mg; 1 product/source], chews [100 mg; 1 product/source], and liquid suspensions or solution [6 mg/mL {2 sources} and 50 mg/mL {1 source}]). PROCEDURES Doxycycline content was measured in 5 samples of each tablet, chew, or capsule formulation and 5 replicates/bottle of liquid formulation on days 1 and 21 by liquid chromatography and compared with US Pharmacopeia acceptable ranges. RESULTS All FDA-approved formulations had acceptable content on days 1 and 21. On day 1, mean doxycycline content for the 3 compounded tablet formulations was 89%, 98%, and 116% (3/5, 5/5, and 1/5 samples within acceptable ranges); day 21 content range was 86% to 112% (1/5, 5/5, and 4/5 samples within acceptable ranges). Day 1 content of chews was 81%, 78%, and 98% (0/5, 0/5, and 5/5 samples within acceptable ranges), and that of compounded liquids was 50%, 52%, and 85% (no results within acceptable ranges). No chews or compounded liquid formulations met USP standards on day 21. CONCLUSIONS AND CLINICAL RELEVANCE FDA-approved doxycycline should be prescribed when possible. Whole tablets yielded the most consistent doxycycline content for compounded formulations.

Impact of Flow Rate, Collection Devices, and Extraction Methods on Tear Concentrations Following Oral Administration of Doxycycline in Dogs and Cats.

PubMed

Sebbag, Lionel; Showman, Lucas; McDowell, Emily M; Perera, Ann; Mochel, Jonathan P

2018-04-30

Compare the precision of doxycycline quantification in tear fluid collected with either Schirmer strips or polyvinyl acetal (PVA) sponges following oral drug administration. Three dogs and 3 cats were administered doxycycline orally at a dose of 4.2-5 mg/kg every 12 h for 6 consecutive days. At day 5 and 6, blood and tear fluid were sampled to capture doxycycline trough and maximal concentrations. Tear fluid was collected 3 times (spaced 10 min apart) at each session with the absorbent material placed in the lower conjunctival fornix until the 20-mm mark was reached (Schirmer strip, one eye) or for 1 min (PVA sponge, other eye). Tear extraction was performed with either centrifugation or elution in methanol. Doxycycline concentrations were measured with liquid chromatography-mass spectrometry. Low (100 ng/mL) and high (1,000 ng/mL) tear concentrations measured in vivo were spiked into each absorbent material in vitro to evaluate percentage drug recovery. After oral administration of doxycycline, the drug reached the tear compartment at concentrations of 45.1-900.7 ng/mL in cats and 45.4-632.0 ng/mL in dogs, representing a tear-to-serum ratio of 12% and 16%, respectively. Doxycycline tear concentrations were significantly more precise when tear collection was performed with Schirmer strips rather than PVA sponges (P = 0.007), but were not correlated with tear flow rate. In vitro doxycycline recovery was poor to moderate (<75%). Schirmer strips represent a good option for lacrimal doxycycline quantification, although the collection and subsequent extraction have to be optimized to improve drug recovery.

The effect of locally delivered doxycycline as an adjunctive therapy to scaling and root planing in smokers

PubMed Central

Al Hulami, Hassan; Babay, Nadir; Awartani, Fatin; Anil, Sukumaran

2011-01-01

Background Locally delivered doxycycline is found to be effective in managing periodontitis as an adjunct to scaling and root planing. Aim To evaluate the effect of locally delivered doxycycline (10%) with scaling and root planing in the periodontal treatment of smokers and to compare it with scaling and root planing alone. Methods Twelve smokers with chronic periodontitis and a pocket depth (⩾5 mm) on posterior teeth that bleed on probing were selected. Patients were randomly assigned to scaling and root planing (SRP) or scaling and root planing followed by local application of doxycycline (SRP-D). Plaque, bleeding on probing, gingival recession, clinical attachment level (CAL), and probing depth (PD) were recorded at the baseline, 6 and 12 weeks. Results Both groups showed a significant reduction in Plaque, Bleeding on Probing and pocket depth at 6th and 12th week from the baseline. A statistically significant gain of attachment was observed in both groups after treatment. Even though the doxycycline group showed slightly higher attachment gain it was not statistically significant compared to the control group. Conclusion The observations of the study reveal that the additional benefit of topical application of doxycycline as an adjunct to scaling and root planing in smokers is not convincing. However, further clinical studies may be necessary to substantiate the present observations. PMID:23960508

Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma.

PubMed

Miladi, Imen; Vivier, Magali; Dauplat, Marie-Mélanie; Chatard, Morgane; Besse, Sophie; Vidal, Aurélien; Chassain, Karine; Jean, Betty; Forestier, Christiane; Chezal, Jean-Michel; Rédini, Francoise; Degoul, Francoise; Miot-Noirault, Elisabeth

2017-09-01

This study was conducted during the development of innovative treatment targeting the microenvironment of chondrosarcoma. In this context, MMP inhibitors were conjugated with a quaternary ammonium (QA) function as a targeting ligand to proteoglycans of chondrosarcoma extracellular matrix. Here we report the proof of concept of this strategy applied to the MMP13 inhibitor, doxycycline (Dox). A quaternary ammonium derivative of the MMP13 inhibitor doxycycline (QA-Dox) was synthesized, and its anticancer activity was evaluated in the Swarm rat chondrosarcoma (SRC) model compared with the parent drug doxycycline, in vitro and in vivo. In vivo, dox and QA-Dox efficiency was assessed at equimolar doses according to a q4dx4 schedule by monitoring tumour volume by MRI and PG-targeted scintigraphy. Molecular mechanism (MMP13 expression, proteoglycan level) and histology studies were performed on tumours. The link of QA targeting function to Dox maintained the MMP13 inhibitory activity in vitro. Interestingly, the bacteriostatic activity was lost. SRC cells incubated with both drugs were blocked in S and G2 M phases. Tumour growth inhibition (confirmed by histology) was observed for both Dox and QA-Dox. Undesirable blood effects (leukocyte decrease) were reduced when Dox was targeted to tumour tissue using the QA function. In the SRC model, the MMP13 inhibitor Dox and its QA derivative are promising as adjuvant therapies for chondrosarcoma management.

Prospective open-label evaluation of long-term low-dose doxycycline for difficult-to-treat chronic rhinosinusitis with nasal polyps.

PubMed

Pinto Bezerra Soter, A C; Bezerra, T F; Pezato, R; Teles Abdo, T R; Pilan, R M; Pinna, F R; Gevaert, P; van Zele, T; Bachert, C; Voegels, R L

2017-06-01

This study aimed to assess clinical outcomes of long-term low-dose oral doxycycline therapy in difficult-to-treat chronic rhinosinusitis with polyps (CRSwNP). This was a prospective, open-label study of 60 patients with difficult-to-treat CRSwNP who had undergone endoscopic sinus surgery. Patients were divided into two groups: 28 received nasal steroids, saline irrigation, and doxycycline (200 mg on the first day, followed by 100 mg once daily) for 12 weeks, while 30 received only nasal steroids and saline irrigation. The main outcome measure was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Other outcome measures were the SNOT-20, NOSE, and Lund-Kennedy scores. The following parameters were also analyzed: asthma, rhinitis, non-steroidal-exacerbated respiratory disease (NERD), and baseline serum IgG, IgA, IgE, IgM, ANCA, and eosinophil count. There was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Patients who received doxycycline also had significantly better outcomes regarding SNOT-20, NOSE, and Lund-Kennedy scores. There was a negative association among a clinically significant improvement of SNOT-20 and presence of asthma, NERD, and elevated serum IgE levels before treatment. These findings suggest that doxycycline may have a beneficial role for CRSwNP patients, especially for patients without asthma, NERD or high levels of serum IgE before treatment.

Observed Treatment Responses to Short-Course Doxycycline Therapy for Rectal Lymphogranuloma Venereum in Men Who Have Sex With Men.

PubMed

Simons, Rebecca; Candfield, Sophie; French, Patrick; White, John A

2018-06-01

Lymphogranuloma venereum (LGV) has reestablished itself as an endemic sexually transmitted infection in the United Kingdom and elsewhere in Europe and North America over the last decade. Current guidelines suggest treatment with 21 days of doxycycline; however, the evidence base for LGV treatment including its duration is very limited. We conducted a retrospective review in 2 central London genitourinary medicine clinics of men who have sex with men (MSM) with LGV in whom less than 21 days of doxycycline was used initially. Sixty MSM were treated initially with less than 21 days of doxycycline, of whom 50 (83%) were prescribed a 7-day course. Fifty percent of patients were asymptomatic, with the rest having rectal or other symptoms. Fifty-nine (97%) of 60 had a negative test of cure for LGV at a median of 31 days (7-200 days). Reinfection as opposed to treatment failure was considered likely in the patient testing positive. A second test of cure at a median of 139 days later (37-638 days) was completed in 30 patients, of whom 28 (93%) were negative for LGV. Seven to 14 days of doxycycline is effective in most cases of LGV with negative TOCs in 59 of 60 patients. These data suggest that 7 days of doxycycline is effective in achieving cure of rectal LGV in most MSM. There is a case for a randomized controlled trial of LGV treatment including a 7-day regimen of doxycycline.

Preoperative doxycycline does not decolonize Propionibacterium acnes from the skin of the shoulder: a randomized controlled trial.

PubMed

Namdari, Surena; Nicholson, Thema; Parvizi, Javad; Ramsey, Matthew

2017-09-01

Propionibacterium acnes is frequently cultured in patients undergoing both primary and revision shoulder surgery. The purpose of this study was to evaluate the efficacy and safety of preoperative oral administration of doxycycline in decreasing the colonization of skin around the shoulder by P. acnes. This was a single-institution, prospective, randomized controlled trial of male patients undergoing shoulder arthroscopy. Patients were randomized to receive oral doxycycline (100 mg twice a day) for 7 days or to the standard of care (no drug). Before skin incision, 2 separate 3-mm punch biopsy specimens were obtained from the sites of the anterior and posterior arthroscopic portals and were sent for culture in anaerobic and aerobic medium held for 13 days. There were 22 of 37 (59.5%) patients in the no-drug group and 16 of 37 (43.2%) patients in the doxycycline group who had at least 1 dermal culture positive for P. acnes (P = .245). In the no-drug group, 10 patients (45.5%) had 1 positive culture and 12 (54.5%) had 2 positive cultures (34 total positive cultures [45.9%]). In the doxycycline group, 6 (37.5%) patients had 1 positive culture and 10 (62.5%) had 2 positive cultures (26 total positive cultures [35.1%]; P = .774). Administration of oral doxycycline for 7 days before surgery did not reduce colonization of P. acnes significantly. Given the potential risk for emergence of bacterial resistance and the adverse effects associated with administration of antibiotics, we do not recommend routine use of oral doxycycline for preoperative decolonization of the shoulder. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells

PubMed Central

Alexander-Savino, Carolina V.; Hayden, Matthew S.; Richardson, Christopher; Zhao, Jiyong; Poligone, Brian

2016-01-01

Cutaneous T-cell Lymphoma (CTCL) is a rare non-Hodgkin's lymphoma that can affect the skin, blood, and lymph nodes, and can metastasize at late stages. Novel therapies that target all affected disease compartments and provide longer lasting responses while being safe are needed. One potential therapeutic target is NF-λB, a regulator of immune responses and an important participant in carcinogenesis and cancer progression. As a transcription factor, NF-λB targets genes that promote cell proliferation and survival. Constitutive or aberrant activation of NF-λB is encountered in many types of cancer, including CTCL. Recently, while analyzing gene-expression profiles of a variety of small molecule compounds that target NF-λB, we discovered the tetracycline family of antibiotics, including doxycycline, to be potent inhibitors of the NF-λB pathway. Doxycycline is well-tolerated, safe, and inexpensive; and is commonly used as an antibiotic and anti-inflammatory for the treatment a multitude of medical conditions. In our current study, we show that doxycycline induces apoptosis in a dose dependent manner in multiple different cell lines from patients with the two most common subtypes of CTCL, Mycosis Fungoides (MF) and Sézary Syndrome (SS). Similar results were found using primary CD4+ T cells from a patient with SS. Doxycycline inhibits TNF induced NF-λB activation and reduces expression of NF-λB dependent anti-apoptotic proteins, such as BCL2α. Furthermore, we have identified that doxycycline induces apoptosis through reactive oxygen species. PMID:27732942

Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells.

PubMed

Alexander-Savino, Carolina V; Hayden, Matthew S; Richardson, Christopher; Zhao, Jiyong; Poligone, Brian

2016-11-15

Cutaneous T-cell Lymphoma (CTCL) is a rare non-Hodgkin's lymphoma that can affect the skin, blood, and lymph nodes, and can metastasize at late stages. Novel therapies that target all affected disease compartments and provide longer lasting responses while being safe are needed. One potential therapeutic target is NF-κB, a regulator of immune responses and an important participant in carcinogenesis and cancer progression. As a transcription factor, NF-κB targets genes that promote cell proliferation and survival. Constitutive or aberrant activation of NF-κB is encountered in many types of cancer, including CTCL.Recently, while analyzing gene-expression profiles of a variety of small molecule compounds that target NF-κB, we discovered the tetracycline family of antibiotics, including doxycycline, to be potent inhibitors of the NF-κB pathway. Doxycycline is well-tolerated, safe, and inexpensive; and is commonly used as an antibiotic and anti-inflammatory for the treatment a multitude of medical conditions.In our current study, we show that doxycycline induces apoptosis in a dose dependent manner in multiple different cell lines from patients with the two most common subtypes of CTCL, Mycosis Fungoides (MF) and Sézary Syndrome (SS). Similar results were found using primary CD4+ T cells from a patient with SS. Doxycycline inhibits TNF induced NF-κB activation and reduces expression of NF-κB dependent anti-apoptotic proteins, such as BCL2α. Furthermore, we have identified that doxycycline induces apoptosis through reactive oxygen species.

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial.

PubMed

Cerisano, Giampaolo; Buonamici, Piergiovanni; Parodi, Guido; Santini, Alberto; Moschi, Guia; Valenti, Renato; Migliorini, Angela; Colonna, Paolo; Bellandi, Benedetta; Gori, Anna Maria; Antoniucci, David

2017-08-01

Metalloproteinases inhibition by doxycycline reduces cardiac protein degradation at extracellular and intracellular level in the experimental model ischemia/reperfusion injury. Since both extracellular cardiac matrix and titin filaments inside the cardiomyocyte are responsible for the myocardial stiffness, we hypothesized that doxycycline could favorably act on left ventricular (LV) filling pressures in patients after reperfused acute ST-elevation myocardial infarction (STEMI). Seventy-three of 110 patients of the TIPTOP trial underwent a 2D-Echo-Doppler on admission, and at pre-discharge and at 6-month after a primary PCI for STEMI and LV dysfunction. From admission to pre-discharge, LV filling changed from a high filling pressure (HFP) to a normal filling pressure (NFP) pattern in 91% of the doxycycline-group, and in 67% of the control-group. Conversely, 1% of the doxycycline-group, and 37% of the control-group changed the LV filling from NFP to HFP pattern. Overall, a pre-discharge HFP pattern was present in 4 patients (11%) of the doxycycline-group and in 13 patients (36%) of the control-group (p=0.025). The evaluation of metalloproteinases and their tissue inhibitors plasma concentrations provide possible favorable action of doxycycline. On the multivariate analyses, troponine I peak (p=0.026), doxycycline (p=0.033), and on admission to pre-discharge LVEF changes (p=0.044) were found to be associated with pre-discharge HFP pattern. Independently of their baseline LV filling behavior, the 6-month remodeling was less in patients with pre-discharge NFP pattern than in patients with HFP pattern. In patients with STEMI and LV dysfunction doxycycline can favorably modulate the LV filling pattern early after primary PCI. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Thermodynamic studies of iron chelation with doxycycline in acidic medium

NASA Astrophysics Data System (ADS)

Javed, Javeria; Zahir, Erum

2017-06-01

Doxycycline (DOX) is a broad-spectrum tetracycline antibiotic synthetically derived from oxytetracycline. The complex formation of this drug with iron(III) was studied using spectrophotometry. The thermodynamic parameters of the systems were calculated using the changes in the absorption spectra which occur due to hydrogen bond or complex formation. Thermodynamic parameters of the formation of iron(III) complex with doxycycline (Δ H, Δ G, Δ S, and stability constants) were determined spectrophotometrically at a wavelength corresponding to absorption maximum (374.5 nm) at three different temperatures (22, 35, and 45°C). The obtained data show that the complex has metal to ligand molar ratio of 1: 2 at pH 2-3. The stability constants were calculated to be 13.99 × 106, 7.06 × 105, and 1.29 × 106 by mole ratio method at 22, 35, and 45°C, respectively.

Doxycycline Impairs Mitochondrial Function and Protects Human Glioma Cells from Hypoxia-Induced Cell Death: Implications of Using Tet-Inducible Systems.

PubMed

Luger, Anna-Luisa; Sauer, Benedikt; Lorenz, Nadja I; Engel, Anna L; Braun, Yannick; Voss, Martin; Harter, Patrick N; Steinbach, Joachim P; Ronellenfitsch, Michael W

2018-05-17

Inducible gene expression is an important tool in molecular biology research to study protein function. Most frequently, the antibiotic doxycycline is used for regulation of so-called tetracycline (Tet)-inducible systems. In contrast to stable gene overexpression, these systems allow investigation of acute and reversible effects of cellular protein induction. Recent reports have already called for caution when using Tet-inducible systems as the employed antibiotics can disturb mitochondrial function and alter cellular metabolism by interfering with mitochondrial translation. Reprogramming of energy metabolism has lately been recognized as an important emerging hallmark of cancer and is a central focus of cancer research. Therefore, the scope of this study was to systematically analyze dose-dependent metabolic effects of doxycycline on a panel of glioma cell lines with concomitant monitoring of gene expression from Tet-inducible systems. We report that doxycycline doses commonly used with inducible expression systems (0.01⁻1 µg/mL) substantially alter cellular metabolism: Mitochondrial protein synthesis was inhibited accompanied by reduced oxygen and increased glucose consumption. Furthermore, doxycycline protected human glioma cells from hypoxia-induced cell death. An impairment of cell growth was only detectable with higher doxycycline doses (10 µg/mL). Our findings describe settings where doxycycline exerts effects on eukaryotic cellular metabolism, limiting the employment of Tet-inducible systems.

Suppressive antibiotic therapy with oral doxycycline for Staphylococcus aureus prosthetic joint infection: a retrospective study of 39 patients.

PubMed

Pradier, M; Nguyen, S; Robineau, O; Titecat, M; Blondiaux, N; Valette, M; Loïez, C; Beltrand, E; Dézeque, H; Migaud, H; Senneville, E

2017-09-01

The aim of this study was to describe the use of oral doxycycline as suppressive antibiotic therapy (SAT) in patients with Staphylococcus aureus periprosthetic (hip or knee) joint infections. The medical charts of all patients with surgical revisions for S. aureus hip or knee prosthetic joint infections (PJIs) who were given doxycycline-based SAT because of a high risk of failure of various origins were reviewed. Data regarding tolerability and effectiveness of doxycycline-based SAT were analysed. A total of 39 patients (mean age 66.1 ± 16.3 years) received doxycycline-base SAT in the period from January 2006 to January 2014. PJIs involved the hip in 23 patients (59.0%) and the knee in 16 (41.0%), and were qualified as early in 15 patients (38.5%). Methicillin-resistant S. aureus (MRSA) accounted for 22% of the total number of bacterial strains identified. All patients included in the study had surgery, which consisted of debridement and implant retention in 32 (82.1%). Adverse events likely attributable to SAT were reported in six patients (15.4%), leading to discontinuation of SAT in three (7.7%). A total of 29 patients (74.4%) remained event-free and 10 (25.6%) failed, including 8 (20.5%) relapses and 2 (5.1%) superinfections. Overall, 8 of the 10 failure cases were related to a doxycycline-susceptible pathogen. These results suggest that oral doxycycline used as SAT in patients treated for S. aureus hip or knee PJIs has an acceptable tolerability and effectiveness and appears to be a reasonable option in this setting. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Clinical and microbiological effects of a subantimicrobial dose of oral doxycycline on periodontitis in dogs.

PubMed

Kim, S E; Hwang, S Y; Jeong, M; Lee, Y; Lee, E R; Park, Y W; Ahn, J S; Kim, S; Seo, K

2016-02-01

Doxycycline is regarded as an effective treatment for periodontal inflammation. In humans, it has been shown that the long-term administration of a subantimicrobial dose of doxycycline (SDD) does not induce antimicrobial effects on the subgingival microflora and furthermore does not affect antimicrobial susceptibility. The present study was designed to evaluate the influence of oral administration of SDD on normal periodontal microflora and antimicrobial susceptibility in dogs. Experimental periodontitis was induced in 12 experimental dogs using a silk and wire-twisted ligature for 60 days. After the periodontitis induction period, the ligature was removed, and dental cleaning (subgingival and supragingival ultrasonic scaling) was performed. The dogs were randomly assigned to one of two groups: an SDD group with six dogs receiving 2 mg/kg PO once daily and a control group with six dogs receiving a placebo. At weeks 0, 4 and 8, clinical periodontal parameters were evaluated. After the clinical assessments, subgingival plaque was sampled and then cultured in an anaerobic system for one week, and the total anaerobes, Porphyromonas spp., Bacteroides spp. and Pasteurella spp. counts were investigated. Using the agar dilution method, the minimum bactericidal concentration of doxycycline was evaluated and the resistance for doxycycline was monitored during this experimental phase. The clinical periodontal status of the SDD group was significantly improved compared to the control group (P <0.05). Bacterial counts were not significantly different between the two experimental groups (P > 0.05), and antibacterial resistance was not established in the SDD group during the experimental periods (P <0.05). These results suggest that the once daily oral regimen of 2 mg/kg of doxycycline could serve as a SDD in dogs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Doxycycline synergizes with doxorubicin to inhibit the proliferation of castration-resistant prostate cancer cells.

PubMed

Zhu, Chao; Yan, Xueting; Yu, Ao; Wang, Yongjian

2017-11-01

Castration-resistant prostate cancer (CRPC) is fatal and there is currently no effective clinical treatment. The antibiotic doxycycline has shown anti-cancer effect in several kinds of solid tumors including prostate cancer. In this study, a combination of doxycycline and doxorubicin was used to investigate the synergistic effect on CRPC cells. MTT assay was employed to determine the viability of cells in two-dimensional (2D) cultures. Apoptosis was determined by Annexin V/propidium iodide (PI) double staining assay. Cell cycle was analyzed by PI staining, and reverse transcription-PCR (RT-PCR) was used to determine the expressions of apoptosis-related genes at mRNA level. Western blot analysis was used to analyze the expressions of Bcl-2, Bax, and Poly (ADP-ribose) polymerase proteins. Cytotoxicity assay and morphological observation of PC3 cells in three-dimensional (3D) cultures were used to determine the effect of combination treatment. Results showed that doxycycline combined with doxorubicin significantly inhibited PC3 cells in both 2D and 3D cultures, enhanced apoptosis, and increased the accumulation of cells in G2/M phase. RT-PCR showed down-regulation of Bcl-2 and up-regulation of Bax mRNA after combination treatment. Meanwhile, western blot analysis showed that combination treatment resulted in down-regulation of Bcl-2 protein and up-regulation of Bax protein, and that PARP cleavage was obviously exhibited after combination treatment. Confocal imaging analysis indicated that doxorubicin penetrated deeply into the core of spheroids when combined with doxycycline. These data indicated that doxycycline in combination with doxorubicin had a synergistic effect on PC3 cells and may provide a potential novel strategy for the treatment of CRPC. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For

Matrix metalloproteinase activity in stifle synovial fluid of cranial cruciate ligament deficient dogs and effect of postoperative doxycycline treatment.

PubMed

Rabillard, M; Danger, R; Doran, I P; Niebauer, G W; Brouard, S; Gauthier, O

2012-07-01

This prospective clinical study investigated the activity of matrix metalloproteinases (MMPs) in stifle synovial fluid (SF) of 13 dogs with acute cranial cruciate ligament (CCL) rupture, and the effect of a postoperative doxycycline treatment. MMP-2, 3, 9 and 13 activities were compared with respect to the time of sampling (preoperatively or 1 month after surgical stabilisation) and the type of postoperative adjuvant treatment (doxycycline or not). No significant activity was detected for both MMP-3 and MMP-13. MMP-2 and MMP-9 activities were found to be significantly highly increased in SF of CCL ruptured stifles compared to control stifles of unaffected dogs. No significant effect from surgical stabilisation and postoperative doxycycline treatment on MMP-2 and MMP-9 activities was found, indicating that doxycycline may not be an appropriate postoperative medical treatment after CCL rupture. Copyright © 2011 Elsevier Ltd. All rights reserved.

Interplay between three RND efflux pumps in doxycycline-selected strains of Burkholderia thailandensis.

PubMed

Biot, Fabrice Vincent; Lopez, Mélanie Monique; Poyot, Thomas; Neulat-Ripoll, Fabienne; Lignon, Sabrina; Caclard, Arnaud; Thibault, François Michel; Peinnequin, Andre; Pagès, Jean-Marie; Valade, Eric

2013-01-01

Efflux systems are involved in multidrug resistance in most Gram-negative non-fermentative bacteria. We have chosen Burkholderia thailandensis to dissect the development of multidrug resistance phenotypes under antibiotic pressure. We used doxycycline selection to obtain several resistant B. thailandensis variants. The minimal inhibitory concentrations of a large panel of structurally unrelated antibiotics were determined ± the efflux pump inhibitor phenylalanine-arginine ß-naphthylamide (PAßN). Membrane proteins were identified by proteomic method and the expressions of major efflux pumps in the doxycycline selected variants were compared to those of the parental strains by a quantitative RT-PCR analysis. Doxycycline selected variants showed a multidrug resistance in two major levels corresponding to the overproduction of two efflux pumps depending on its concentration: AmrAB-OprA and BpeEF-OprC. The study of two mutants, each lacking one of these pumps, indicated that a third pump, BpeAB-OprB, could substitute for the defective pump. Surprisingly, we observed antagonistic effects between PAßN and aminoglycosides or some ß-lactams. PAßN induced the overexpression of AmrAB-OprA and BpeAB-OprB pump genes, generating this unexpected effect. These results may account for the weak activity of PAßN in some Gram-negative species. We clearly demonstrated two antagonistic effects of this molecule on bacterial cells: the blocking of antibiotic efflux and an increase in efflux pump gene expression. Thus, doxycycline is a very efficient RND efflux pump inducer and PAßN may promote the production of some efflux pumps. These results should be taken into account when considering antibiotic treatments and in future studies on efflux pump inhibitors.

Gene silencing in Escherichia coli using antisense RNAs expressed from doxycycline-inducible vectors.

PubMed

Nakashima, N; Tamura, T

2013-06-01

Here, we report on the construction of doxycycline (tetracycline analogue)-inducible vectors that express antisense RNAs in Escherichia coli. Using these vectors, the expression of genes of interest can be silenced conditionally. The expression of antisense RNAs from the vectors was more tightly regulated than the previously constructed isopropyl-β-D-galactopyranoside-inducible vectors. Furthermore, expression levels of antisense RNAs were enhanced by combining the doxycycline-inducible promoter with the T7 promoter-T7 RNA polymerase system; the T7 RNA polymerase gene, under control of the doxycycline-inducible promoter, was integrated into the lacZ locus of the genome without leaving any antibiotic marker. These vectors are useful for investigating gene functions or altering cell phenotypes for biotechnological and industrial applications. A gene silencing method using antisense RNAs in Escherichia coli is described, which facilitates the investigation of bacterial gene function. In particular, the method is suitable for comprehensive analyses or phenotypic analyses of genes essential for growth. Here, we describe expansion of vector variations for expressing antisense RNAs, allowing choice of a vector appropriate for the target genes or experimental purpose. © 2013 The Society for Applied Microbiology.

Doxycycline and sulfadimethoxine transfer from cross-contaminated feed to chicken tissues.

PubMed

Segato, G; Benetti, C; Angeletti, R; Montesissa, C; Biancotto, G

2011-01-01

During feed preparation at feed mills or during feed mixing in bins at farms, the accidental contamination of feed at trace levels by veterinary drug residues, commonly known as carry-over, can accidentally but frequently occur. To evaluate the concentrations of residual antimicrobials in poultry edible tissues, due to contaminated feed, sulfadimethoxine and doxycycline were administered for 10 days to chickens in poultry feed incurred at the contamination levels frequently found during national feed monitoring programmes (1-5 mg kg(-1)). Sulfadimethoxine and doxycycline residual concentrations detected in muscle (

Systematic Review and Meta-Analysis of Doxycycline Efficacy for Rectal Lymphogranuloma Venereum in Men Who Have Sex with Men

PubMed Central

Leeyaphan, Charussri; Ong, Jason J.; Chow, Eric P.F.; Kong, Fabian Y.S.; Hocking, Jane S.; Bissessor, Melanie; Fairley, Christopher K.

2016-01-01

Rectal lymphogranuloma venereum (LGV) has reemerged as a sexually transmitted infection among men who have sex with men (MSM), particularly those who are HIV-positive. We undertook a systematic review and meta-analysis to determine the efficacy of doxycycline (100 mg 2×/d for 21 days) for rectal LGV in MSM. Nine studies were included: 4 prospective, 4 retrospective, and 1 combined retrospective and prospective. In total, 282 MSM with rectal LGV were included in the studies. All studies reported using nucleic acid amplification tests to assess microbial cure. Most patients (>80%) had symptomatic rectal infection. The fixed-effects pooled efficacy for doxycycline was 98.5% (95% CI 96.3%–100%, I2 = 0%; p = 0.993). Doxycycline at 100 mg twice daily for 21 days demonstrated a high microbial cure rate. These data support doxycycline at this dosage and duration as first-line therapy for rectal LGV in MSM. PMID:27513890

Systematic Review and Meta-Analysis of Doxycycline Efficacy for Rectal Lymphogranuloma Venereum in Men Who Have Sex with Men.

PubMed

Leeyaphan, Charussri; Ong, Jason J; Chow, Eric P F; Kong, Fabian Y S; Hocking, Jane S; Bissessor, Melanie; Fairley, Christopher K; Chen, Marcus

2016-10-01

Rectal lymphogranuloma venereum (LGV) has reemerged as a sexually transmitted infection among men who have sex with men (MSM), particularly those who are HIV-positive. We undertook a systematic review and meta-analysis to determine the efficacy of doxycycline (100 mg 2×/d for 21 days) for rectal LGV in MSM. Nine studies were included: 4 prospective, 4 retrospective, and 1 combined retrospective and prospective. In total, 282 MSM with rectal LGV were included in the studies. All studies reported using nucleic acid amplification tests to assess microbial cure. Most patients (>80%) had symptomatic rectal infection. The fixed-effects pooled efficacy for doxycycline was 98.5% (95% CI 96.3%-100%, I (2)  = 0%; p = 0.993). Doxycycline at 100 mg twice daily for 21 days demonstrated a high microbial cure rate. These data support doxycycline at this dosage and duration as first-line therapy for rectal LGV in MSM.

Evaluation of three-layered doxycycline-collagen loaded nanofiber wound dressing.

PubMed

Tort, Serdar; Acartürk, Füsun; Beşikci, Arzu

2017-08-30

Nanofiber wound dressings have great potential for both acute and chronic wound healing. The aim of this study is to develop a wound dressing by the electrospinning method and to determine its in vitro characteristics. The viscosity and the surface tension values of the polymer solutions used in the electrospinning were measured and their suitability for electrospinning was evaluated. Nanofiber wound dressing consists of three layers. The first and the second layers are sodium alginate and chitosan nanofibers, respectively. The core of the coaxial nanofibers that comprises the third layer of the wound dressing contains 1% polycaprolactone and 4.5% collagen, the shell comprises 2.5% doxycycline and 2.5% polyethylene oxide. The developed wound dressing comprises aligned nanofibers, with a contact angle of 38°, a work of bioadhesion value of 0.485mJ/cm 2 on rat skin, a tensile strength of 2.76MPa, an elongation at break value of 7.65%, a specific surface area of 9.65m 2 /g and a porosity of 52.3%. The amount of doxycycline content was found to be 260μg/cm 2 and the complete drug release was achieved in 15min. No cytotoxic effect was shown in cell culture studies with keratinocyte cell lines. As a result of the stability studies, it was found that the morphological, mechanical, bioadhesion and wettability properties and the amount of doxycycline remained stable for a period of 12 months at 4°C/ambient humidity condition. The developed three-layered wound dressing could be an alternative for wound healing applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Sustained Simultaneous Delivery of Metronidazole and Doxycycline From Polycaprolactone Matrices Designed for Intravaginal Treatment of Pelvic Inflammatory Disease.

PubMed

Pathak, Meenakshi; Coombes, Allan G A; Ryu, BoMi; Cabot, Peter J; Turner, Mark S; Palmer, Cheryn; Wang, Dongjie; Steadman, Kathryn J

2018-03-01

Poly(ɛ-caprolactone) (PCL) intravaginal matrices were produced for local delivery of a combination of antibacterials, by rapidly cooling a mixture of drug powders dispersed in PCL solution. Matrices loaded with different combinations of metronidazole (10%, 15%, and 20% w/w) and doxycycline (10% w/w) were evaluated in vitro for release behavior and antibacterial activity. Rapid "burst release" of 8%-15% of the doxycycline content and 31%-37% of the metronidazole content occurred within 24 h when matrices were immersed in simulated vaginal fluid at 37°C. The remaining drug was extracted gradually over 14 days to a maximum of 65%-73% for doxycycline and 62%-71% for metronidazole. High levels of antibacterial activity up to 89%-91% against Gardnerella vaginalis and 84%-92% against Neisseria gonorrhoeae were recorded in vitro for release media collected on day 14, compared to "nonformulated" metronidazole and doxycycline solutions. Based on the in vitro data, the minimum levels of doxycycline and metronidazole released from PCL matrices in the form of intravaginal rings into vaginal fluid in vivo were predicted to exceed the minimum inhibitory concentrations for N. gonorrhea (reported range 0.5-4.0 μg/mL) and G. vaginalis (reported range 2-12.8 μg/mL) respectively, which are 2 of the major causative agents for pelvic inflammatory disease. Copyright © 2018. Published by Elsevier Inc.

Comparative pharmacokinetics of a new oral long-acting formulation of doxycycline hyclate: A canine clinical trial.

PubMed

Arciniegas Ruiz, Sara Melisa; Gutiérrez Olvera, Lilia; Bernad Bernad, María Josefa; Caballero Chacón, Sara Del Carmen; Vargas Estrada, Dinorah

2015-12-01

Doxycicline is used in dogs as treatment of several bacterial infections, mycoplasma, chlamydia and rickettsial diseases. However, it requires long treatments and several doses to be effective. The aim of this study was to determine the pharmacokinetics of four formulations of doxycycline hyclate, administered orally, with different proportions of excipients, acrylic acid-polymethacrylate-based matrices, to obtain longer therapeutic levels than conventional formulation. Forty-eight dogs were randomly assigned in five groups to receive a single oral dose (20mg/kg) of doxycycline hyclate without excipients (control) or a long-acting formulation containing doxycycline, acrylic acid polymer, and polymethacrylate in one of the following four proportions: DOX1(1:0.25:0.0035), DOX2(1:0.5:0.0075), DOX3 (1:1:0.015), or DOX4(1:2:0.0225). Temporal profiles of serum concentrations were obtained at several intervals after each treatment. Therapeutic concentrations were observed for 60h for DOX1 and DOX4, 48h for DOX2 and DOX3 and only 24h for DOX-C. None of the pharmacokinetic parameter differed significantly between DOX1 and DOX2 or between DOX3 and DOX4; however, the findings for the control treatment were significantly different compared to all four long-acting formulations. Results indicated that DOX1 had the most adequate pharmacokinetic-pharmacodynamic relationships for a time-dependent drug and had longer release times than did doxycycline alone. However, all four formulations can be effective depend on the minimum effective serum doxycycline concentration of the microorganism being treated. These results suggest that the use of any of these formulations can reduce the frequency of administration, the patient's stress, occurrence of adverse effects and the cost of treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficiency of Nanotube Surface-Treated Dental Implants Loaded with Doxycycline on Growth Reduction of Porphyromonas gingivalis.

PubMed

Ferreira, Cimara Fortes; Babu, Jegdish; Hamlekhan, Azhang; Patel, Sweetu; Shokuhfar, Tolou

The prevalence of peri-implant infection in patients with dental implants has been shown to range from 28% to 56%. A nanotube-modified implant surface can deliver antibiotics locally and suppress periodontal pathogenic bacterial growth. The aim of this study was to evaluate the deliverability of antibiotics via a nanotube-modified implant. Dental implants with a nanotube surface were fabricated and loaded with doxycycline. Afterward, each dental implant with a nanotube surface was placed into 2-mL tubes, removed from solution, and placed in a fresh solution daily for 28 days. Experimental samples from 1, 2, 4, 16, 24, and 28 days were used for this evaluation. The concentration of doxycycline was measured using spectrophotometric analysis at 273-nm absorbance. The antibacterial effect of doxycycline was evaluated by supplementing Porphyromonas gingivalis (P gingivalis) growth media with the solution collected from the dental implants at the aforementioned time intervals for a period of 48 hours under anaerobic conditions. A bacterial viability assay was used to evaluate P gingivalis growth at 550-nm absorbance. Doxycycline concentration varied from 0.33 to 1.22 μg/mL from day 1 to day 28, respectively. A bacterial viability assay showed the highest P gingivalis growth at day 1 (2 nm) and the lowest at day 4 (0.17 nm), with a gradual reduction from day 1 to day 4 of approximately 87.5%. The subsequent growth pattern was maintained and slightly increased from baseline in approximately 48.3% from day 1 to day 24. The final P gingivalis growth measured at day 28 was 29.4% less than the baseline growth. P gingivalis growth was suppressed in media supplemented with solution collected from dental implants with a nanotube surface loaded with doxycycline during a 28-day time interval.

Doxycycline for outpatient-treated acute exacerbations of COPD: a randomised double-blind placebo-controlled trial.

PubMed

van Velzen, Patricia; Ter Riet, Gerben; Bresser, Paul; Baars, Jeroen J; van den Berg, Bob T J; van den Berg, Jan W K; Brinkman, Paul; Dagelet, Jennece W F; Daniels, Johannes M A; Groeneveld-Tjiong, Dewi R G L; Jonkers, René E; van Kan, Coen; Krouwels, Frans H; Pool, Karin; Rudolphus, Arjan; Sterk, Peter J; Prins, Jan M

2017-06-01

Antibiotics do not reduce mortality or short-term treatment non-response in patients receiving treatment for acute exacerbations of COPD in an outpatient setting. However, the long-term effects of antibiotics are unknown. The aim of this study was to investigate if the antibiotic doxycycline added to the oral corticosteroid prednisolone prolongs time to next exacerbation in patients with COPD receiving treatment for an exacerbation in the outpatient setting. In this randomised double-blind placebo-controlled trial, we recruited a cohort of patients with COPD from outpatient clinics of nine teaching hospitals and three primary care centres in the Netherlands. Inclusion criteria were an age of at least 45 years, a smoking history of at least 10 pack-years, mild-to-severe COPD (Global Initiative of Chronic Obstructive Lung Disease [GOLD] stage 1-3), and at least one exacerbation during the past 3 years. Exclusion criteria were poor mastery of the Dutch language, poor cognitive functioning, known allergy to doxycycline, pregnancy, and a life expectancy of shorter than 1 month. If a participant had an exacerbation, we randomly assigned them (1:1; with permuted blocks of variable sizes [ranging from two to ten]; stratified by GOLD stage 1-2 vs 3) to a 7 day course of oral doxycycline 100 mg daily (200 mg on the first day) or placebo. Exclusion criteria for randomisation were fever, admission to hospital, and current use of antibiotics or use within the previous 3 weeks. Patients in both groups received a 10 day course of 30 mg oral prednisolone daily. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary outcome was time to next exacerbation in all randomly allocated patients except for those incorrectly randomly allocated who did not meet the inclusion criteria or met the exclusion criteria. This trial is registered with the Netherlands Trial Register, number NTR2499. Between Dec 22, 2010, and Aug 6, 2013, we randomly

Retreatment rates for uncomplicated gonorrhea infection: comparing ceftriaxone and azithromycin versus ceftriaxone and doxycycline.

PubMed

Schumacher, Christina M; Ghanem, Khalil G

2013-07-01

The current recommended first-line regimen to treat gonorrhea is ceftriaxone in combination with either azithromycin or doxycycline. Azithromycin is the preferred second agent. We retrospectively measured and compared gonorrhea retreatment rates between patients receiving ceftriaxone plus azithromycin and those receiving ceftriaxone plus doxycycline. Using data from public sexually transmitted disease clinics for patients treated for gonorrhea in Baltimore, Maryland, between January 2004 and December 2011, we measured time to retreatment from the date the ceftriaxone regimen was received. Censoring occurred on the earlier of 2 years posttreatment or March 31, 2012. Survival analysis methods were used to compare retreatment rates. One tenth (9.9%; n = 4457) of patients were retreated within 2 years. Treatment regimen was not related to time to retreatment (adjusted hazard ratio [aHR], 0.88; 95% confidence interval, 0.69-1.12). Patients receiving expedited partner therapy (EPT) were 45% less likely to be retreated (aHR, 0.55 [0.31-0.96]) compared with patients treated before EPT became available. A subanalysis among patients retested for gonorrhea within 90 and 30 days found retreatment rates of 18.8% (n = 91/485) and 13.5% (n = 19/140), respectively. The 90-day cohort showed no association with treatment regimen (aHR, 0.95 [0.55-1.65]); however, all of the retreated patients in the 30-day cohort had received the doxycycline regimen. Gonorrhea retreatment was common, highlighting the need for rescreening and better partner therapies. The protective effect of EPT further underscores the need for effective oral therapies. Azithromycin may be preferable as the second agent to treat gonorrhea, although doxycycline seems to be a reasonable alternative.

The efficacy of azithromycin and doxycycline for the treatment of rectal chlamydia infection: a systematic review and meta-analysis.

PubMed

Kong, Fabian Yuh Shiong; Tabrizi, Sepehr N; Fairley, Christopher Kincaid; Vodstrcil, Lenka A; Huston, Wilhelmina M; Chen, Marcus; Bradshaw, Catriona; Hocking, Jane S

2015-05-01

There are increasing concerns about treatment failure following treatment for rectal chlamydia with 1 g of azithromycin. A systematic review and meta-analysis was conducted to investigate the efficacy of 1 g of azithromycin as a single dose or 100 mg of doxycycline twice daily for 7 days for the treatment of rectal chlamydia. Medline, Embase, PubMed, Cochrane Controlled Trials Register, Australia New Zealand Clinical Trial Register and ClinicalTrials.gov were searched to the end of April 2014. Studies using 1 g of azithromycin or 7 days of doxycycline for the treatment of rectal chlamydia were eligible. Gender, diagnostic test, serovar, symptomatic status, other sexually transmitted infections, follow-up time, attrition and microbial cure were extracted. Meta-analysis was used to calculate pooled (i) azithromycin and doxycycline efficacy and (ii) efficacy difference. All eight included studies were observational. The random-effects pooled efficacy for azithromycin (based on eight studies) was 82.9% (95% CI 76.0%-89.8%; I(2) = 71.0%; P < 0.01) and for doxycycline (based on five studies) was 99.6% (95% CI 98.6%-100%; I(2) = 0%; P = 0.571), resulting in a random-effects pooled efficacy difference (based on five studies) of 19.9% (95% CI 11.4%-28.3%; I(2) = 48.5%; P = 0.101) in favour of doxycycline. The efficacy of single-dose azithromycin may be considerably lower than 1 week of doxycycline for treating rectal chlamydia. However, the available evidence is very poor. Robust randomized controlled trials are urgently required. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The cre-inducer doxycycline lowers cytokine and chemokine transcript levels in the gut of mice.

PubMed

Hansen, Axel Kornerup; Malm, Sara Astrup; Metzdorff, Stine B

2017-11-01

The antibiotic doxycycline is used as an inducer of recombinase (cre)-based conditional gene knockout in mice, which is a common tool to show the effect of disrupted gene functions only in one period of a research animal's life. However, other types of such antibiotics have been shown to have a strong impact on the immune system. Here we show that in C57BL/6 mice, the most commonly applied strain for genetic modification, doxycycline treatment lowered transcription of the genes Il1b, Il10, Il18, Tnf, Cxcl1, and Cxcl2 in the ileum, and of the gene Il18 in colon. Cytokines and chemokines encoded by these genes are important in the disease expression in a range of mouse models. Although protein abundances only rarely correlate 100% to transcript levels, and the net result, therefore, may be less dramatic, it seems reasonable to be aware that a broad spectrum antibiotic, such as doxycycline, may impact the transgenic animal in ways unrelated to the activation of the gene deletion.

Doxycycline in the treatment of respiratory tract infections. Results of a pan-European multi-centre trial.

PubMed

Pestel, M

1975-01-01

In the winter of 1973-4, general practitioners from seven European countries took part in a multi-centre trial of doxycycline in the treatment of infections of the respiratory tract. The carefully designed protocol was observed by all participants. A total of 1,747 patients were admitted to the trial; their ages ranged from 6 years to over 80. The commonest diagnoses (50%) were acute bronchitis and acute exacerbations of chronic bronchitis. On the recommended dosage of 200 mg doxycycline on the first day, followed by 100 mg daily thereafter (though 200 mg could be continued daily in severe cases), 87% of patients achieved good or very good results. Both subjective (pain) and objective (sputum volume and viscosity, temperature, cough) measures showed rapid improvement, usually by the third to fifth days. Side-effects were minimal and mainly gastrointestinal and caused only 4 patients to discontinue treatment. Overall, doxycycline proved its effectiveness and rapidity of action.

DOMINO, doxycycline 40 mg vs. minocycline 100 mg in the treatment of rosacea: a randomized, single-blinded, noninferiority trial, comparing efficacy and safety.

PubMed

van der Linden, M M D; van Ratingen, A R; van Rappard, D C; Nieuwenburg, S A; Spuls, Ph I

2017-06-01

There is a lack of evidence for minocycline in the treatment of rosacea. To compare the efficacy and safety of doxycycline 40 mg vs. minocycline 100 mg in papulopustular rosacea. In this randomized, single-centre, 1 : 1 allocation, assessor-blinded, noninferiority trial, patients with mild-to-severe papulopustular rosacea were randomly allocated to either oral doxycycline 40 mg or minocycline 100 mg for a 16-week period with 12 weeks of follow-up. Our primary outcomes were the change in lesion count and change in patient's health-related quality of life (using RosaQoL). Intention-to-treat and per protocol analyses were performed. Of the 80 patients randomized (40 minocycline, 40 doxycycline), 71 were treated for 16 weeks. Sixty-eight patients completed the study. At week 16, the median change in lesion count was comparable in both groups: doxycycline vs. minocycline, respectively 13 vs. 14 fewer lesions. The RosaQoL scores were decreased for both doxycycline and minocycline, respectively by 0·62 and 0·86. Secondary outcomes were comparable except for Investigator's Global Assessment success, which was seen significantly more often in the minocycline group than in the doxycycline group (60% vs. 18%, P < 0·001). At week 28, outcomes were comparable, except for RosaQoL scores and PaGA, which were significantly different in favour of minocycline (P = 0·005 and P = 0·043, respectively), and fewer relapses were recorded in the minocycline group than in the doxycycline group (7% and 48%, respectively; P < 0·001). No serious adverse reactions were reported. Minocycline 100 mg is noninferior to doxycycline 40 mg in efficacy over a 16- week treatment period. At follow-up, RosaQoL and PaGA were statistically significantly more improved in the minocycline group than in the doxycycline group, and minocycline 100 mg gives longer remission. In this study there was no significant difference in safety between these treatments; however, based on previous

Influence of enrofloxacin traces in drinking water to doxycycline tissue pharmacokinetics in healthy and infected by Mycoplasma gallisepticum broiler chickens.

PubMed

Gbylik-Sikorska, Malgorzata; Posyniak, Andrzej; Sniegocki, Tomasz; Sell, Bartosz; Gajda, Anna; Sawicka, Anna; Olszewska-Tomczyk, Monika; Bladek, Tomasz; Tomczyk, Grzegorz; Zmudzki, Jan

2016-04-01

Most of antibiotics, administrated in the treatment of poultry diseases are dissolved in drinking water, and it can lead to water supply systems contamination, especially when the regular cleaning is not using. This situation can lead to unconscious administration of low doses of antibiotics to untreated animals. The aim of this study was to clarify the impact of the exposure of enrofloxacin traces (500 μg l(-1)) to doxycycline pharmacokinetics in healthy and experimentally Mycoplasma gallisepticum infected broiler chickens., Two experimental groups, received of enrofloxacin in water and all groups, received 20 mg kg(-1) bw of doxycycline. The compounds concentrations in muscles and livers were determined by LC-MS/MS. The maximum drug tissue concentration (Cmax) of doxycycline was highest in liver obtained from infected chickens which, received enrofloxacin traces (ENR + DC/MG). It was about 40% higher than in healthy chickens from group I which received only doxycycline. It was found that the concentration-time curve AUC(0-t) values in group ENR + DC/MG were almost 75% higher than in the group (DC) and 35% higher than in group (ENR + DC) which also received enrofloxacin traces. The constant exposure of broiler chickens on enrofloxacin traces as well as infection, may significantly influenced on doxycycline tissue pharmacokinetic profile. Copyright © 2016 Elsevier Ltd. All rights reserved.

Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species

PubMed Central

González-Lizárraga, Florencia; Socías, Sergio B.; Ávila, César L.; Torres-Bugeau, Clarisa M.; Barbosa, Leandro R. S.; Binolfi, Andres; Sepúlveda-Díaz, Julia E.; Del-Bel, Elaine; Fernandez, Claudio O.; Papy-Garcia, Dulce; Itri, Rosangela; Raisman-Vozari, Rita; Chehín, Rosana N.

2017-01-01

Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy per se is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses. Our results show that doxycycline reshapes α-synuclein oligomers into off-pathway, high-molecular-weight species that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different β-sheet structural arrangement. These structural changes affect the α-synuclein ability to destabilize biological membranes, cell viability, and formation of additional toxic species. Altogether, these mechanisms could act synergically giving novel targets for repurposing this drug. PMID:28155912

Sulfur and nitrogen binary doped carbon dots derived from ammonium thiocyanate for selective probing doxycycline in living cells and multicolor cell imaging.

PubMed

Xue, Mingyue; Zhang, Liangliang; Zhan, Zhihua; Zou, Mengbing; Huang, Yong; Zhao, Shulin

2016-04-01

A novel sulfur and nitrogen binary doped carbon dots (S,N-CDs) was synthesized by one-step manner through the hydrothermal treatment of citric acid (CA) and ammonium thiocyanate, and the procedures for biomedical applications, including probing doxycycline in living cells and multicolor cell imaging were developed. The obtained S,N-CDs are stable in aqueous solution, possess a very high quantum yield (QY, 74.15%) and good photostability. The fluorescence of S,N-CDs can be specifically quenched by doxycycline, providing a convenient turn-off assay of doxycycline. This assay shows a wide linear detection range from 0.08 to 60 μM with a low detection limit of 20 nM. The present method also displays a good selectivity. More importantly, the S,N-CDs have an excellent biocompatibility and low cytotoxicity, allowing the multicolor cell imaging and doxycycline detection in living cells. Consequently, the developed doxycycline methods is facile, low-cost, biocompatible, sensitive and selective, which may hold the potential applications in the fields of food safety and environmental monitoring, as well as cancer therapy and related mechanism research. Copyright © 2015 Elsevier B.V. All rights reserved.

IL-1α and MMP-9 Tear Levels of Patients with Active Ocular Rosacea before and after Treatment with Systemic Azithromycin or Doxycycline.

PubMed

Lam-Franco, Lorena; Perfecto-Avalos, Yocanxochitl; Patiño-Ramírez, Beatriz E; Rodríguez García, Alejandro

2018-06-06

The purpose of this paper was to determine the lacrimal concentration of IL-1α and MMP-9 in patients with active ocular rosacea before and after systemic treatment with azithromycin or doxycycline. After 4 weeks of therapy with azithromycin (500 mg/day, 3 days a week PO) or doxycycline (200 mg/day PO), lacrimal samples were analyzed using an enzyme-linked immunosorbent assay multiplex. There was a significant difference between baseline IL-1α (37.9 pg/mL) and MMP-9 (26.7 ng/mL) in rosacea eyes compared to controls (0.001 pg/mL for IL-1α and 0.2 ng/mL for MMP-9) (p < 0.001). IL-1α decreased from 47.0 pg/mL before azithromycin to 23.5 pg/mL after treatment (p = 0.024), but not after doxycycline therapy. On the contrary, baseline MMP-9 tear levels (10.28 ng/mL) decreased after treatment (8.36 pg/mL) with doxycycline (p = 0.054) but not with azithromycin. There was a strong clinical correlation of higher baseline IL-1α tear levels between patients who responded to doxycycline therapy and those who failed (p = 0.043). Patients unresponsive to azithromycin had significantly higher baseline MMP-9 levels than those with doxycycline (p = 0.040). While IL-1α levels decreased after azithromycin therapy, MMP-9 did so after doxycycline treatment. Baseline cytokine tear levels tend to be markedly elevated in patients with antibiotic failure, suggesting their potential role as therapeutic biomarkers for the disease. © 2018 S. Karger AG, Basel.

Effect of doxycycline on transforming growth factor-beta-1-induced matrix metalloproteinase 2 expression, migration, and collagen contraction in nasal polyp-derived fibroblasts.

PubMed

Shin, Jae-Min; Park, Joo-Hoo; Kang, Byungjin; Lee, Seoung-Ae; Park, Il-Ho; Lee, Heung-Man

2016-11-01

It is well known that doxycycline has antibacterial and anti-inflammatory effects. In this study, we aimed to investigate the effects of doxycycline on the transforming growth factor (TGF) beta 1-induced matrix metalloproteinase (MMP) 2 expression, migration, and collagen contraction, and to determine its molecular mechanism on nasal polyp-derived fibroblasts (NPDF). NPDFs were isolated from the nasal polyps of six patients. Doxycycline was used to pretreat TGF-beta-1-induced NPDFs and ex vivo organ cultures of nasal polyps. Cytotoxicity was evaluated by using a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Smad2/3 is one of the major transcription factors of TGF-beta signaling. The expression levels of MMP2 and Smad2/3 were measured by using Western blotting, reverse transcription-polymerase chain reaction, and immunofluorescence staining. The enzymic activity of MMP2 was analyzed by using gelatin zymography. Fibroblast migration was evaluated by using transwell migration assays. Contractile activity was measured by a collagen gel contraction assay. The expression level of MMP2 in nasal polyp tissues increased in comparison with inferior turbinate tissues. TGF-beta-1-induced NPDFs were not affected by doxycycline (0-40 μg/mL). The expression levels of MMP2 and activation of Smad2/3 in TGF-beta-1-induced NPDFs and in organ cultures of nasal polyps were significantly downregulated with doxycycline pretreatment. Doxycycline also reduced TGF-beta-1-induced fibroblast migration and collagen contraction in NPDFs. Doxycycline inhibited TGF-beta-1-induced MMP2 expression, migration, and collagen contraction via the Smad2/3 signal pathways in NPDFs.

Use of quartz crystal nanobalance to study the binding and stabilization of albumin and doxycycline on a thin layer of hydroxyapatite

NASA Astrophysics Data System (ADS)

Victor, Sunita Prem; Sharma, Chandra P.; Sreenivasan, K.

2011-12-01

This study reports the use of quartz crystal nanobalance (QCN) to study the adsorption of two model molecules namely albumin and doxycycline by hydroxyapatite (HA). The work focuses on the deposition of a stable coating of HA on the quartz crystal, modification of the coating using doxycycline and its subsequent effects on albumin adsorption. The uniformity and thickness of the HA coating has been studied using atomic force microscopy (AFM). The functional groups to ascertain the presence of the selected moieties have been characterized by Raman spectroscopy. The results indicate that the mass of albumin deposited on the surface of the HA coated quartz crystal functionalized with doxycycline shows a substantial increase when compared to the standard HA coated quartz crystal. The adsorbed albumin has also been found to be retained for an enhanced period of time. This surface immobilization of doxycycline and subsequent albumin adsorption seem to be a promising approach to confer biomaterials with antithrombogenic and antibacterial surfaces.

Effect of antibiotics on clinical, pathologic and immunologic responses in murine Potomac horse fever: protective effects of doxycycline.

PubMed

Rikihisa, Y; Jiang, B M

1989-03-01

Effects of three antibiotics on clinical, pathologic and immunologic responses in murine Potomac horse fever caused by Ehrlichia risticii infection were examined. When antibiotics were given after the development of clinical signs, antibiotics ranked in the order of reducing clinical signs and in preventing body weight loss and an intestinal enlargement were doxycycline, demeclocycline and rifampin. Infected mice treated with doxycycline and demeclocycline developed greater splenomegaly than rifampin-treated or untreated infected mice. All antibiotics used prevented thymic atrophy due to E. risticii infection. Indirect fluorescent antibody titers were highest with doxycycline treatment. Mice treated with demeclocycline and rifampin produced higher antibody titer than those without treatment. Ehrlichia risticii was reisolated from the spleens of both untreated and rifampin-treated infected mice. The effects of administering single doses of doxycycline at different times after infection were examined. Body weight loss was prevented by the drug given at every treatment day examined, i.e. Days 3, 5 and 7 post-infection (PI). Thymic atrophy was minimum in mice treated at Day 5 PI, while splenomegaly was found on every treatment day. Splenocyte proliferative response to concanavalin A and lipopolysaccharide, and specific antibody development against E. risticii was best in mice treated at Day 5 PI followed by those treated at Day 3 and Day 7 PI.

Addition of doxycycline to ciprofloxacin for infection prophylaxis during autologous stem cell transplants for multiple myeloma.

PubMed

Sivik, J M; Davidson, J; Hale, C M; Drabick, J J; Talamo, G

2018-03-21

The most commonly used antibacterial prophylaxis during autologous stem cell transplants (ASCT) for multiple myeloma (MM) involves a fluoroquinolone, such as ciprofloxacin or levofloxacin. We assessed the impact of adding doxycycline to ciprofloxacin as routine antibacterial prophylaxis in these patients. We retrospectively reviewed electronic medical records and our ASCT database to analyze rates and types of bacterial infections in MM patients who underwent ASCT in our institution. Among 419 patients, 118 received ciprofloxacin alone (cipro group), and 301 ciprofloxacin and doxycycline (cipro-doxy group). Neutropenic fever (NF) developed in 63 (53%) and 108 (36%) patients of the cipro and cipro-doxy groups, respectively (p = 0.010). The number of documented bacteremic episodes was 13 (11%) and 14 (4.7%) in the two groups, respectively (p = 0.017). Antimicrobial resistance and Clostridium difficile infections were uncommon. Transplant-related mortality was 1% in both groups. The addition of doxycycline to standard prophylaxis with ciprofloxacin seems to reduce the number of NF episodes and documented bacterial infections in patients with MM undergoing ASCT, without increasing rate of serious complications.

Evaluation of safety of lipomer doxycycline hydrochloride (lipomer DH).

PubMed

Dhumal, Rohit; Soni, Mahesh; Devarajan, Padma; Samad, Abdul; Gaikwad, Rajiv; Vanage, Geeta

2011-02-01

The nanoparticulate formulation of lipomer doxycycline hydrochloride (lipomer DH) has been synthesized for the treatment of Brucellosis to increase efficacy of the drug. The present study was undertaken to determine the intravenous safety of blank lipomer and Lipomer DH in terms of maximum tolerated dose in rats. It was observed that blank lipomer and lipomer DH were safe when administered intravenously at doses 2000 mg/kg Bw and 18 mg/kg bw respectively.

Oral doxycycline for the prevention of postoperative trachomatous trichiasis in Ethiopia: a randomised, double-blind, placebo-controlled trial.

PubMed

Habtamu, Esmael; Wondie, Tariku; Aweke, Sintayehu; Tadesse, Zerihun; Zerihun, Mulat; Gashaw, Bizuayehu; Roberts, Chrissy H; Kello, Amir Bedri; Mabey, David C W; Rajak, Saul N; Callahan, E Kelly; Macleod, David; Weiss, Helen A; Burton, Matthew J

2018-05-01

Trachomatous trichiasis is treated surgically to prevent sight loss. Unfavourable surgical outcomes remain a major challenge. We investigated the hypothesis that doxycycline might reduce the risk of postoperative trichiasis following surgery in patients with trachomatous trichiasis through anti-matrix metalloproteinase and anti-inflammatory activity. In this randomised, double-blind, placebo-controlled trial, adults (aged >18 years) with upper lid trachomatous trichiasis in association with tarsal conjunctive scarring were recruited through community-based screening and surgical outreach campaigns in Ethiopia. Individuals who had previously had eyelid surgery were excluded. Participants were randomly assigned (1:1), with random block sizes of four or six, to receive oral doxycycline (100 mg once a day) or placebo for 28 days immediately after trichiasis surgery. Randomisation was stratified by surgeon. Patients, investigators, surgeons, and all other study team members were masked to study group allocation and treatment. Participants were examined at 10 days, and 1, 6, and 12 months after surgery. The primary outcome was the cumulative proportion of individuals who developed postoperative trichiasis by 12 months. Primary analyses were done in all participants who attended at least one of the four follow-up assessments. Safety analyses were done in all participants who attended either the 10 day or 1 month follow-up assessments. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201512001370307. Between Dec 21, 2015, and April 6, 2016, 1000 patients with trichiasis were enrolled and randomly assigned to treatment (499 patients to doxycycline, 501 patients to placebo). All but one participant attended at least one follow-up assessment. Thus, 999 participants were assessed for the primary outcome: 498 in the doxycycline group and 501 in the placebo group. By month 12, 58 (12%) of 498 patients in the doxycycline group and 62 (12%) of

Influence of microplastics on the toxicity of the pharmaceuticals procainamide and doxycycline on the marine microalgae Tetraselmis chuii.

PubMed

Prata, Joana C; Lavorante, Beatriz R B O; B S M Montenegro, Maria da Conceição; Guilhermino, Lúcia

2018-04-01

Microplastics and pharmaceuticals are considered ubiquitous and emergent pollutants of high concern but the knowledge on their effects on primary producers is still limited, especially those caused by mixtures. Thus, the goal of the present study was to investigate if the presence of microplastics (1-5 μm diameter) influences the toxicity of the pharmaceuticals procainamide and doxycycline to the marine microalga Tetraselmis chuii. Bioassays (96 h) to investigate the toxicity of those substances individually and in mixtures (i.e. microplastics-procainamide mixtures and microplastics-doxycycline mixtures) were carried out. Effect criteria were the average specific growth rate (growth rate) and chlorophyll a concentration (chlorophyll). EC 10 , EC 20 and EC 50 were determined. Microplastics alone had no significant effects on growth rate up to 41.5 mg/l, whereas chlorophyll was significantly reduced at 0.9 and 2.1 mg/l of microplastics, but not at higher concentrations. The 96 h EC 50 (growth rate and chlorophyll, respectively) determined for the other bioassays were: 104 and 143 mg/l for procainamide alone; 125 and 31 mg/l for procainamide in the presence of microplastics; 22 and 14 mg/l for doxycycline alone; 11 and 7 mg/l for doxycycline in the presence of microplastics. Significant differences (p < 0.001) between the toxicity curves of each pharmaceutical alone and in mixture with microplastics were found for procainamide (chlorophyll), and doxycycline (both parameters). Thus, both pharmaceuticals were toxic to T. chuii in the low ppm range, and microplastics-pharmaceutical mixtures were more toxic than the pharmaceuticals alone. Very high decreases of doxycycline concentrations in test media were found, indicating degradation of the antibiotic. Thus, although the biological results are expressed in relation to doxycycline concentration, the effects were likely caused by a mixture of the parental compound and its degradation products. The

Synergy of combined Doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models

PubMed Central

2010-01-01

Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. We had previously shown that doxycycline administered for 3 months at 40 mg/Kg/ml in the drinking water, was capable of removing TTR amyloid deposits present in stomachs of old TTR-V30M transgenic mice; the removal was accompanied by a decrease in extracellular matrix remodeling proteins that accompany fibrillar deposition, but not of non-fibrillar TTR deposition and/or markers associated with pre-fibrillar deposits. On the other hand, Tauroursodeoxycholic acid (TUDCA), a biliary acid, administrated to the same mouse model was shown to be effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages. In the present work we evaluated different doxycycline administration schemes, including different periods of treatment, different dosages and different FAP TTR V30M animal models. Evaluation included CR staining, immunohistochemistry for TTR, metalloproteinase 9 (MMP-9) and serum amyloid P component (SAP). We determined that a minimum period of 15 days of treatment with a 8 mg/Kg/day dosage resulted in fibril removal. The possibility of intermittent treatments was also assessed and a maximum period of 15 days of suspension was determined to maintain tissues amyloid-free. Combined cycled doxycycline and TUDCA administration to mice with amyloid deposition, using two different concentrations of both drugs, was more effective than either individual doxycycline or TUDCA, in significantly lowering TTR deposition and associated tissue markers. The observed synergistic effect of doxycycline/TUDCA in the range of human tolerable quantities, in the transgenic TTR mice models prompts their application in FAP, particularly in the early stages of disease. PMID:20673327

Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells

PubMed Central

Lee, Ming-Jen; Hung, Shih-Hsuan; Huang, Mu-Ching; Tsai, Tsuimin

2017-01-01

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo. PMID:28558025

Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells.

PubMed

Lee, Ming-Jen; Hung, Shih-Hsuan; Huang, Mu-Ching; Tsai, Tsuimin; Chen, Chin-Tin

2017-01-01

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo.

Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.

PubMed

Schmidt, Karin; Gardill, Bernd R; Kern, Alina; Kirchweger, Peter; Börsch, Michael; Muller, Yves A

2018-05-14

The allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member α1-antichymotrypsin. Further engineering allowed exploitation of the proteinase-triggered serpin-typical S-to-R transition to modulate the ligand affinities. These design variants follow strategies observed in naturally occurring plasma globulins that allow for the targeted delivery of hormones in the blood. By analogy, we propose that the variants described in the present study could be further developed to allow for the delivery of the antibiotic doxycycline and the anticancer compound doxorubicin to tissues/locations that express specific proteinases, such as bacterial infection sites or tumor cells secreting matrix metalloproteinases.

Cytotoxicity of Doxycycline Effluent Generated by the Fenton Process

PubMed Central

Borghi, Alexandre Augusto; Stephano, Marco Antônio; Monteiro de Souza, Paula; Alves Palma, Mauri Sérgio

2014-01-01

This study aims at determining the Minimum Inhibitory Concentration with Escherichia coli ATCC 25922 and cytotoxicity to L929 cells (ATCC CCL-1) of the waste generated by doxycycline degradation by the Fenton process. This process has shown promise in this treatment thanks mainly to the fact that the waste did not show any relevant inhibitory effect on the test organism and no cytotoxicity to L-929 cells, thus demonstrating that the antibiotic properties were inactivated. PMID:25379532

Doxycycline for prevention of erlotinib-induced rash in patients with non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial.

PubMed

Deplanque, Gaël; Gervais, Radj; Vergnenegre, Alain; Falchero, Lionel; Souquet, Pierre-Jean; Chavaillon, Jean-Michel; Taviot, Bruno; Fraboulet, Ghislaine; Saal, Hakim; Robert, Caroline; Chosidow, Olivier

2016-06-01

Rash is a common epidermal growth factor receptor inhibitor-induced toxicity that can impair quality of life and treatment compliance. We sought to evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer. This open-label, randomized, prospective, phase II trial was conducted in 147 patients with locally advanced or metastatic non-small-cell lung cancer progressing after first-line chemotherapy, randomized for 4 months with erlotinib alone 150 mg/d per os (control arm) or combined with doxycycline 100 mg/d (doxycycline arm). Incidence and severity of rash, compliance, survival, and safety were assessed. Baseline characteristics of the 147 patients were well balanced in the intent-to-treat population. Folliculitis occurred in 71% of patients in the doxycycline arm and 81% in the control arm (P = .175). The severity of folliculitis and other skin lesions was lower in the doxycycline arm compared with the control arm. Other adverse events were reported at a similar frequency across arms. There was no significant difference in survival between treatment arms. The open-label design of the study and the duration of the treatment with doxycycline are limitations. Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial.

PubMed

Williams, Hywel C; Wojnarowska, Fenella; Kirtschig, Gudula; Mason, James; Godec, Thomas R; Schmidt, Enno; Chalmers, Joanne R; Childs, Margaret; Walton, Shernaz; Harman, Karen; Chapman, Anna; Whitham, Diane; Nunn, Andrew J

2017-04-22

Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3-5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on

The etiology of community-acquired pneumonia in Australia: why penicillin plus doxycycline or a macrolide is the most appropriate therapy.

PubMed

Charles, Patrick G P; Whitby, Michael; Fuller, Andrew J; Stirling, Robert; Wright, Alistair A; Korman, Tony M; Holmes, Peter W; Christiansen, Keryn J; Waterer, Grant W; Pierce, Robert J P; Mayall, Barrie C; Armstrong, John G; Catton, Michael G; Nimmo, Graeme R; Johnson, Barbara; Hooy, Michelle; Grayson, M L

2008-05-15

Available data on the etiology of community-acquired pneumonia (CAP) in Australia are very limited. Local treatment guidelines promote the use of combination therapy with agents such as penicillin or amoxycillin combined with either doxycycline or a macrolide. The Australian CAP Study (ACAPS) was a prospective, multicenter study of 885 episodes of CAP in which all patients underwent detailed assessment for bacterial and viral pathogens (cultures, urinary antigen testing, serological methods, and polymerase chain reaction). Antibiotic agents and relevant clinical outcomes were recorded. The etiology was identified in 404 (45.6%) of 885 episodes, with the most frequent causes being Streptococcus pneumoniae (14%), Mycoplasma pneumoniae (9%), and respiratory viruses (15%; influenza, picornavirus, respiratory syncytial virus, parainfluenza virus, and adenovirus). Antibiotic-resistant pathogens were rare: only 5.4% of patients had an infection for which therapy with penicillin plus doxycycline would potentially fail. Concordance with local antibiotic recommendations was high (82.4%), with the most commonly prescribed regimens being a penicillin plus either doxycycline or a macrolide (55.8%) or ceftriaxone plus either doxycycline or a macrolide (36.8%). The 30-day mortality rate was 5.6% (50 of 885 episodes), and mechanical ventilation or vasopressor support were required in 94 episodes (10.6%). Outcomes were not compromised by receipt of narrower-spectrum beta-lactams, and they did not differ on the basis of whether a pathogen was identified. The vast majority of patients with CAP can be treated successfully with narrow-spectrum beta-lactam treatment, such as penicillin combined with doxycycline or a macrolide. Greater use of such therapy could potentially reduce the emergence of antibiotic resistance among common bacterial pathogens.

In vitro study on the effect of doxycycline on the microbial activity of soil determined by redox-potential measuring system.

PubMed

Szakmár, Katalin; Reichart, Olivér; Szatmári, István; Erdősi, Orsolya; Szili, Zsuzsanna; László, Noémi; Székely Körmöczy, Péter; Laczay, Péter

2014-09-01

The potential effect of doxycycline on the microbial activity was investigated in three types of soil. Soil samples were spiked with doxycycline, incubated at 25°C and tested at 0, 2, 4 and 6 days after treatment. The microbiological activity of the soil was characterized by the viable count determined by plate pouring and by the time necessary to reach a defined rate of the redox-potential decrease termed as time to detection (TTD).The viable count of the samples was not changed during the storage. The TTD values, however exhibited a significant increase in the 0.2-1.6 mg/kg doxycycline concentration range compared to the untreated samples indicating concentration-dependent inhibitory effect on microbial activity. The potency of the effect was different in the 3 soil types. To describe the combined effect of the doxycycline concentration and time on the biological activity of one type of soil a mathematical model was constructed and applied.The change of microbial metabolic rate could be measured also without (detectable) change of microbial count when the traditional microbiological methods are not applicable. The applied new redox potential measurement-based method is a simple and useful procedure for the examination of microbial activity of soil and its potential inhibition by antibiotics.

Would Parents Consent to a Comparative Effectiveness Trial of Oral Doxycycline Versus Intravenous Ceftriaxone for the Treatment of Children with Lyme Meningitis?

PubMed

Garro, Aris; Koster, Michael; LaRue, Molly; Hipolito, Evelyn; Congdon, Elizabeth; Burnett, Kathleen; Cullen, Nicole; Nigrovic, Lise E

2018-05-01

Children with Lyme meningitis are often treated with intravenous ceftriaxone, although oral doxycycline may be effective. Parents were surveyed after observing a video describing a hypothetical Lyme meningitis treatment trial. Eighty-four of 102 (82%) would consent to their child participating. Parents would accept 2 additional days of symptoms (noninferiority margin) with doxycycline even if ceftriaxone hastened symptom resolution.

Treatment Outcomes for Rectal Lymphogranuloma Venereum in Men Who Have Sex with Men Using Doxycycline, Azithromycin, or Both: A Review of Clinical Cases.

PubMed

Leeyaphan, Charussri; Ong, Jason J; Chow, Eric P F; Dimovski, Karolina; Kong, Fabian Y S; Hocking, Jane S; Howden, Ben; Bissessor, Melanie; Fairley, Christopher K; Bradshaw, Catriona; Read, Timothy; Chen, Marcus

2017-04-01

Treatment for rectal lymphogranuloma venereum where doxycycline 100 mg twice daily for 21 days was used-either alone or together with azithromycin 1 g single dose-resulted in microbiological cure of 97%. These data support doxycycline 100 mg twice daily for 21 days as the preferred treatment for rectal lymphogranuloma venereum.

The effect of measuring serum doxycycline concentrations on clinical outcomes during treatment of chronic Q fever.

PubMed

van Roeden, S E; Bleeker-Rovers, C P; Kampschreur, L M; de Regt, M J A; Vermeulen Windsant, A; Hoepelman, A I M; Wever, P C; Oosterheert, J J

2018-04-01

First choice treatment for chronic Q fever is doxycycline plus hydroxychloroquine. Serum doxycycline concentration (SDC) >5 μg/mL has been associated with a favourable serological response, but the effect on clinical outcomes is unknown. To assess the effect of measuring SDC during treatment of chronic Q fever on clinical outcomes. We performed a retrospective cohort study, to assess the effect of measuring SDC on clinical outcomes in patients treated with doxycycline and hydroxychloroquine for chronic Q fever. Primary outcome was the first disease-related event (new complication or chronic Q fever-related mortality); secondary outcomes were all-cause mortality and PCR-positivity. Multivariable analysis was performed with a Cox proportional hazards model, with shared-frailty terms for different hospitals included. We included 201 patients (mean age 68 years, 83% male): in 167 patients (83%) SDC was measured, 34 patients (17%) were treated without SDC measurement. First SDC was >5 μg/mL in 106 patients (63%), all with 200 mg doxycycline daily. In patients with SDC measured, dosage was adjusted in 41% (n = 68), concerning an increase in 64 patients. Mean SDC was 4.1 μg/mL before dosage increase, and 5.9 μg/mL afterwards. SDC measurement was associated with a lower risk for disease-related events (HR 0.51, 95% CI 0.26-0.97, P = 0.04), but not with all-cause mortality or PCR-positivity. SDC measurement decreases the risk for disease-related events, potentially through more optimal dosing or improved compliance. We recommend measurement of SDC and striving for SDC >5 μg/mL and <10 μg/mL during treatment of chronic Q fever.

The Effect of Local Delivery Doxycycline and Alendronate on Bone Repair.

PubMed

Limirio, Pedro Henrique Justino Oliveira; Rocha, Flaviana Soares; Batista, Jonas Dantas; Guimarães-Henriques, João César; de Melo, Geraldo Batista; Dechichi, Paula

2016-08-01

The aim of the present study was to investigate the local effect of 10% doxycycline and 1% alendronate combined with poly(lactic-co-glycolic acid) (PLGA) on bone repair. Thirty rats were divided into three groups, as follows: control group (CG), drug group (DG), and vehicle-PLGA group (VG). Bone defect was created in the right femur and filled with the following: blood clot (CG); PLGA gel, 10% doxycycline and 1% alendronate (DG); or vehicle-PLGA (VG). The animals were euthanized 7 or 15 days after surgery. Bone density, bone matrix and number of osteoclasts were quantified. At 7 days, the findings showed increased density in DG (177.75 ± 76.5) compared with CG (80.37 ± 27.4), but no difference compared with VG (147.1 ± 41.5); no statistical difference in bone neoformation CG (25.6 ± 4.8), VG (27.8 ± 4), and DG (18.9 ± 7.8); and decrease osteoclasts in DG (4.6 ± 1.9) compared with CG (26.7 ± 7.4) and VG (17.3 ± 2.7). At 15 days, DG (405.1 ± 63.1) presented higher density than CG (213.2 ± 60.9) and VG (283.4 ± 85.8); there was a significant increase in percentage of bone neoformation in DG (31.5 ± 4.2) compared with CG (23 ± 4), but no difference compared with VG (25.1 ± 2.9). There was a decreased number of osteoclasts in DG (20.7 ± 4.7) and VG (29.5 ± 5.4) compared with CG (40 ± 9.4). The results suggest that the association of 10% doxycycline and 1% alendronate with PLGA-accelerated bone repair.

Mechanistic investigation of doxycycline photosensitization by picosecond-pulsed and continuous wave laser irradiation of cells in culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shea, C.R.; Hefetz, Y.; Gillies, R.

1990-04-15

In order to elucidate the photophysical mechanisms of cellular phototoxicity sensitized by doxycycline, MGH-U1 human bladder carcinoma cells in vitro were treated with 20.7 microM doxycycline and irradiated with either a pulsed (lambda = 355 nm, pulse duration = 24 ps) or a continuous wave (lambda = 351 nm) laser. Cumulative radiant exposure and irradiance were systematically varied in experiments with both lasers. Phototoxicity was assessed by epifluorescence microscopy of unfixed cells using rhodamine 123 labeling of mitochondria. With the continuous wave source, the cumulative radiant exposure required for induction of phototoxic injury was independent of irradiance. With the 24-ps-pulsedmore » source, a significantly lower cumulative radiant exposure was required to induce the phototoxicity when the peak irradiance was 5.8 x 10(7) or 1.3 x 10(8) watts cm-2 compared with when peak irradiance was either lower (6.0 x 10(6) watts cm-2) or higher (7.6 x 10(8) watts cm-2). The measured fluorescence lifetimes of doxycycline in buffered saline solution were longer than the laser pulse duration of 24 ps. The increased efficiency of photosensitization at the optimal peak irradiance in the ps domain appears to result from sequential multiphoton absorption involving higher excited states of the singlet manifold. At the highest irradiance studied, on the other hand, reduced efficiency of photosensitization is attributed to increased photodegradation of doxycycline from higher excited states by processes such as photoionization. A model consistent with these observations is presented along with calculations, based on simple rate equations, that fit the essentials of the proposed model.« less

An outbreak of scrub typhus in military personnel despite protocols for antibiotic prophylaxis: doxycycline resistance excluded by a quantitative PCR-based susceptibility assay.

PubMed

Harris, Patrick N A; Oltvolgyi, Csongor; Islam, Aminul; Hussain-Yusuf, Hazizul; Loewenthal, Mark R; Vincent, Gemma; Stenos, John; Graves, Stephen

2016-06-01

Scrub typhus is caused by the obligate intracellular bacterium Orientia tsutsugamushi and is endemic to many countries in the Asia-Pacific region, including tropical Australia. We describe a recent large outbreak amongst military personnel in north Queensland. A total of 45 clinical cases were identified (36% of all potentially exposed individuals). This occurred despite existing military protocols stipulating the provision of doxycycline prophylaxis. Doxycycline resistance in O. tsutsugamushi has been described in South-East Asia, but not Australia. In one case, O. tsutsugamushi was cultured from eschar tissue and blood. Using quantitative real-time PCR to determine susceptibility to doxycycline for the outbreak strain, a minimum inhibitory concentration (MIC) of ≤0.04 μg/mL was found, indicating susceptibility to this agent. It seems most probable that failure to adhere to adequate prophylaxis over the duration of the military exercise accounted for the large number of cases encountered rather than doxycycline resistance. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial.

PubMed

Cerisano, Giampaolo; Buonamici, Piergiovanni; Gori, Anna Maria; Valenti, Renato; Sciagrà, Roberto; Giusti, Betti; Sereni, Alice; Raspanti, Silvia; Colonna, Paolo; Gensini, Gian Franco; Abbate, Rosanna; Schulz, Richard; Antoniucci, David

2015-10-15

The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Single dosage of doxycycline for prophylaxis against leptospiral infection and leptospirosis during urban flooding in southern Thailand: a non-randomized controlled trial.

PubMed

Chusri, Sarunyou; McNeil, Edward B; Hortiwakul, Thanaporn; Charernmak, Boonsri; Sritrairatchai, Somporn; Santimaleeworagun, Wichai; Pattharachayakul, Sutthiporn; Suksanan, Paritasana; Thaisomboonsuk, Butsaya; Jarman, Richard G

2014-11-01

This study was conducted to investigate the protective efficacy of a single dosage of 200 mg doxycycline against leptospiral infection and leptospirosis and associated risk factors among residents exposed to flooding in southern Thailand. Of 641 participants, 600 received doxycycline while 41 did not. Twenty two participants were infected with Leptospira and six developed leptospirosis. Having a laceration wound was significantly associated with leptospiral infection (odds ratio [OR] = 37.20; P < 0.001) and leptospirosis (OR = 18.24; P = 0.003) whereas exposure to flood more than 3 h per day was associated with only leptospiral infection (OR = 3.70; P = 0.038). Seventeen participants who received doxycycline and five who did not, were infected with Leptospira, resulting a protective efficacy of 76.8% (95% confidence interval [CI] = 34.3%-92.0%). Four who received doxycycline and two who did not, developed leptospirosis, resulting a protective efficacy of 86.3% (CI = -9.8%-98.2%). Among the participants with laceration wound, the protective efficacy for leptospiral infection was 92.0% (CI = 81.2%-96.6%) and for leptospirosis was 95.6% (CI = 78.2%-99.3%). Among the participants exposed to flood water less than or equal to 3 h per day, the protective efficacy for leptospiral infection was 89.2% (95% CI 63.6%-96.67%). A single dosage of 200 mg doxycycline for prophylaxis might be effective for preventing leptospirosis among flood victims with laceration wound after recent flood exposure. Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. All rights reserved.

New intracanal formulations containing doxycycline or chlorhexidine against Enterococcus faecalis.

PubMed

Silva, Ana Rita Marques da; Pinto, Shelon Cristina Souza; Santos, Elizabete Brasil dos; Santos, Fábio André dos; Farago, Paulo Vitor; Gomes, João Carlos; Pina-Vaz, Irene; Carvalho, Manuel Fontes

2014-01-01

The present study aims to evaluate the antimicrobial effect of two new intracanal preparations against E. faecalis. Thirty single-rooted human canine teeth were used. The crowns were removed and the roots were instrumented using a conventional technique. Three groups of ten teeth each were infected with 108 CFU/ ml of E. faecalis for 21 days. The root canals were flled with new intracanal medications containing 3% doxycycline hydrochloride (DX) or 2% chlorhexidine digluconate (CHX). Ten teeth received no medication (NM)-negative control. Microbial samples were obtained 21 days after contamination: 14 days under the effect of the intracanal medications and 7 days after replacing the medications by BHI broth. The samples were homogenized, diluted, seeded on BHI agar and incubated for 48h/36°C. The number of colony forming units (CFU/ml) was obtained and analyzed statistically. All intracanal dressings significantly reduced the number of bacterial cells in the root canal after 14 days with medication. After the period with 7 days with BHI broth, the CFU counts of E. faecalis remained at low values. However, the NM group showed a significant increase of CFU in this period to similar values of the initial contamination. 3% doxycycline hydrochloride gel and 2% CHX gel were effective to eliminate E. faecalis from the root canal system.

Efficacy of subantimicrobial-dose doxycycline against nitrosative stress in chronic periodontitis.

PubMed

Pârvu, Alina Elena; Alb, Sandu Florin; Crăciun, Alexandra; Taulescu, Marian Aurel

2013-02-01

To evaluate the effectiveness of subantimicrobial-dose doxycycline (SDD) as an adjunct to scaling and root planing (SRP) treatment against the nitrosative stress of moderate to advanced chronic periodontitis. Adults with untreated chronic periodontitis (n=174) were randomly administered SRP+SDD (n=87) (20 mg of doxycycline twice daily) or SRP+placebo (n=87) treatment for 3 months. At baseline and after 3 months, the probing depths (PD), bleeding on probing (BOP) and clinical attachment level (CAL) were measured, and a gingivomucosal biopsy was collected to assay the induction of nitric oxide synthase (iNOS) and 3-nitrotyrosine (3NT), and blood was collected to assay for total nitrites and nitrates (NO(x)) and 3NT. Compared to baseline, at the completion of treatment, significant decreases in the levels of tissue iNOS and 3NT and serum NO(x) and 3NT were observed in both groups. SRP+SDD yielded a greater reduction in the gingivomucosal and serum nitrosative stress markers than did SRP+placebo. PD, BOP, and CAL reduction were correlated with the nitrosative stress parameters. On a short-term basis, SDD therapy may be used as an adjunct to SRP treatment against nitrosative stress in moderate to advanced chronic periodontitis.

Brain targeted oral delivery of doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles against ketamine induced psychosis: behavioral, biochemical, neurochemical and histological alterations in mice.

PubMed

Yadav, Monu; Parle, Milind; Sharma, Nidhi; Dhingra, Sameer; Raina, Neha; Jindal, Deepak Kumar

2017-11-01

To develop statistically optimized brain targeted Tween 80 coated chitosan nanoparticulate formulation for oral delivery of doxycycline hydrochloride for the treatment of psychosis and to evaluate its protective effect on ketamine induced behavioral, biochemical, neurochemical and histological alterations in mice. 3 2 full factorial design was used to optimize the nanoparticulate formulation to minimize particle size and maximize entrapment efficiency, while independent variables chosen were concentration of chitosan and Tween 80. The optimized formulation was characterized by particle size, drug entrapment efficiency, Fourier transform infrared, Transmission electron microscopy analysis and drug release behavior. Pure doxycycline hydrochloride (25 and 50 mg/kg, p.o.) and optimized doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles (DCNP opt ) (equivalent to 25 mg/kg doxycycline hydrochloride, p.o.) were explored against ketamine induced psychosis in mice. The experimental studies for DCNP opt , with mean particle size 237 nm and entrapment efficiency 78.16%, elucidated that the formulation successfully passed through blood brain barrier and exhibited significant antipsychotic activity. The underlying mechanism of action was further confirmed by behavioral, biochemical, neurochemical estimations and histopathological study. Significantly enhanced GABA and GSH level and diminished MDA, TNF-α and dopamine levels were observed after administration of DCNP opt at just half the dose of pure doxycycline hydrochloride, showing better penetration of doxycyline hydrochloride in the form of Tween 80 coated nanoparticles through blood brain barrier. This study demonstrates the hydrophilic drug doxycycline hydrochloride, loaded in Tween 80 coated chitosan nanoparticles, can be effectively brain targeted through oral delivery and therefore represents a suitable approach for the treatment of psychotic symptoms.

Use of a doxycycline-enrofloxacin-metronidazole combination with/without diminazene diaceturate to treat naturally occurring canine babesiosis caused by Babesia gibsoni

PubMed Central

2010-01-01

Canine babesiosis is an important worldwide, tick-borne disease caused by hemoprotozoan parasites of the genus Babesia. Babesia gibsoni is the predominant species that causes canine babesiosis in Taipei, Taiwan. It is a small pleomorphic intraerythrocytic parasite that can cause erythrocyte destruction and hemolytic anemia. Efficacy of oral administration of a doxycycline-enrofloxacin-metronidazole combination with and without injections of diminazene diaceturate in the management of naturally occurring canine babesiosis caused by B. gibsoni was evaluated retrospectively. The overall efficacy of this combination of doxycycline-enrofloxacin-metronidazole in conjunction with and without administration of diminazene diaceturate was 85.7% and 83.3%, respectively; with a mean recovery time of 24.2 and 23.5 days, respectively. Concomitant use of intramuscular diminazene diaceturate may not improve the efficacy of a doxycycline-enrofloxacin-metronidazole combination in management of canine babesiosis caused by B. gibsoni. PMID:20416095

Laboratory testing on the removal of the veterinary antibiotic doxycycline during long-term liquid pig manure and digestate storage.

PubMed

Widyasari-Mehta, Arum; Suwito, Hanna Resti Kartika Ayu; Kreuzig, Robert

2016-04-01

The veterinary antibiotic doxycycline (DOXY) is today frequently applied in conventional pig husbandry for the control of respiratory diseases. After the treatment, pigs excrete major amounts of DOXY as the unchanged active substance. Thus, DOXY residues were found in liquid manures and digestates of biogas plants at concentrations of mg kg(-1) dry weight. In order to assess the impact of field applications of contaminated manures and digestates on the entry of DOXY residues into arable and grassland soils, thorough information about the removal of DOXY during long-term storage of farm fertilizers is required. Since this aspect has been only less investigated for manures but not for digestates, first long-term storage simulation tests were performed at laboratory scale. Within the 170-d incubation periods under strictly anaerobic conditions, doxycycline was removed in liquid pig manure by 61% and in digestate by 76%. The calculated half-lives of 120 d and 91 d thus emphasized the persistence of doxycycline in both matrices. Due to the substance specific properties of DOXY, this removal was caused neither by mineralization, epimerization nor biotransformation. According to the high affinity of DOXY to manure and digestate solids, however, the formation of non-extractable residues has to be taken into account as the predominant concentration determining process. This was indicated by the sequential extraction procedure applied. Hence, these results confirmed that a full removal capacity for doxycycline cannot be reached through the long-term storage of farm fertilizers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Outcome of Intravenous Azithromycin Therapy in Patients with Complicated Scrub Typhus Compared with That of Doxycycline Therapy Using Propensity-Matched Analysis

PubMed Central

Jang, Mi-Ok; Jang, Hee-Chang; Kim, Uh Jin; Ahn, Joon Hwan; Kang, Seung-Ji; Jung, Sook-In; Shin, Hee-Young

2014-01-01

There are no well-matched, controlled studies comparing azithromycin with doxycycline for the treatment of complicated scrub typhus. A retrospective propensity score-matched case-control study was performed for patients who presented with complicated scrub typhus and were treated with doxycycline or azithromycin between 2001 and 2011. Data on comorbidities, clinical manifestations, laboratory studies, treatments, and outcomes were extracted for analysis. The clinical characteristics and outcomes of the azithromycin-treated group (n = 73) were compared to those of the doxycycline-treated group (n = 108). Of 181 patients, 73 from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment success and survival rates were not significantly different (89% [65/73 patients] versus 96% [70/73 patients] and 96% [70/73 patients] versus 96% [70/73 patients], respectively [P > 0.05]). No difference was observed in the time to defervescence or length of hospital stay between the two groups (P > 0.05). In complicated scrub typhus patients (n = 181), multivariate analysis showed that only APACHE II score was an independent risk factor for mortality (95% confidence interval, 1.11 to 1.56; P < 0.001). Our data suggest that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients with complicated scrub typhus. PMID:24366734

Doxycycline Leads to Sterility and Enhanced Killing of Female Onchocerca volvulus Worms in an Area With Persistent Microfilaridermia After Repeated Ivermectin Treatment: A Randomized, Placebo-Controlled, Double-Blind Trial

PubMed Central

Debrah, Alexander Yaw; Specht, Sabine; Klarmann-Schulz, Ute; Batsa, Linda; Mand, Sabine; Marfo-Debrekyei, Yeboah; Fimmers, Rolf; Dubben, Bettina; Kwarteng, Alexander; Osei-Atweneboana, Mike; Boakye, Daniel; Ricchiuto, Arcangelo; Büttner, Marcelle; Adjei, Ohene; Mackenzie, Charles D.; Hoerauf, Achim

2015-01-01

Background. Ivermectin (IVM) has been the drug of choice for the treatment of onchocerciasis. However, there have been reports of persistent microfilaridermia in individuals from an endemic area in Ghana after many rounds of IVM, raising concerns of suboptimal response or even the emergence of drug resistance. Because it is considered risky to continue relying only on IVM to combat this phenomenon, we assessed the effect of targeting the Onchocerca volvulus Wolbachia endosymbionts with doxycycline for these individuals with suboptimal response. Methods. One hundred sixty-seven patients, most of them with multiple rounds of IVM, were recruited in areas with IVM suboptimal response and treated with 100 mg/day doxycycline for 6 weeks. Three and 12 months after doxycycline treatment, patients took part in standard IVM treatment. Results. At 20 months after treatment, 80% of living female worms from the placebo group were Wolbachia positive, whereas only 5.1% in the doxycycline-treated group contained bacteria. Consistent with interruption of embryogenesis, none of the nodules removed from doxycycline-treated patients contained microfilariae, and 97% of those patients were without microfilaridermia, in contrast to placebo patients who remained at pretreatment levels (P < .001). Moreover, a significantly enhanced number of dead worms were observed after doxycycline. Conclusions. Targeting the Wolbachia in O. volvulus is effective in clearing microfilariae in the skin of onchocerciasis patients with persistent microfilaridermia and in enhanced killing of adult worms after repeated standard IVM treatment. Strategies can now be developed that include doxycycline to control onchocerciasis in areas where infections persist despite the frequent use of IVM. Clinical Trials Registration. ISRCTN 66649839. PMID:25948064

Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

PubMed Central

Sharma, Raman; Jayoussi, Ghaith Al; Tyrer, Hayley E.; Gamble, Joanne; Hayward, Laura; Guimaraes, Ana F.; Davies, Jill; Waterhouse, David; Cook, Darren A. N.; Myhill, Laura J.; Clare, Rachel H.; Cassidy, Andrew; Steven, Andrew; Johnston, Kelly L.; Ford, Louise; Turner, Joseph D.; Ward, Stephen A.; Taylor, Mark J.

2016-01-01

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis. PMID:26996237

Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial.

PubMed

Keijmel, Stephan P; Delsing, Corine E; Bleijenberg, Gijs; van der Meer, Jos W M; Donders, Rogier T; Leclercq, Monique; Kampschreur, Linda M; van den Berg, Michel; Sprong, Tom; Nabuurs-Franssen, Marrigje H; Knoop, Hans; Bleeker-Rovers, Chantal P

2017-04-15

Approximately 20% of patients with acute Q fever will develop chronic fatigue, referred to as Q fever fatigue syndrome (QFS). The objective of this randomized controlled clinical trial was to assess the efficacy of either long-term treatment with doxycycline or cognitive-behavioral therapy (CBT) in reducing fatigue severity in patients with QFS. Adult patients were included who met the QFS criteria according to the Dutch guideline: a new onset of severe fatigue lasting ≥6 months with significant disabilities, related to an acute Q fever infection, without other somatic or psychiatric comorbidity explaining the fatigue. Using block randomization, patients were randomized between oral study medication and CBT (2:1) for 24 weeks. Second, a double-blind randomization between doxycycline (200 mg/day, once daily) and placebo was performed in the medication group. Primary outcome was fatigue severity at end of treatment (EOT; week 26), assessed with the Checklist Individual Strength subscale Fatigue Severity. Of 155 patients randomized, 154 were included in the intention-to-treat analysis (doxycycline, 52; placebo, 52; CBT, 50). At EOT, fatigue severity was similar between doxycycline (40.8 [95% confidence interval {CI}, 37.3-44.3]) and placebo (37.8 [95% CI, 34.3-41.2]; difference, doxycycline vs placebo, -3.0 [97.5% CI, -8.7 to 2.6]; P = .45). Fatigue severity was significantly lower after CBT (31.6 [95% CI, 28.0-35.1]) than after placebo (difference, CBT vs placebo, 6.2 [97.5% CI, .5-11.9]; P = .03). CBT is effective in reducing fatigue severity in QFS patients. Long-term treatment with doxycycline does not reduce fatigue severity in QFS patients compared to placebo. NCT01318356. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com

Doxycycline reduces the expression and activity of matrix metalloproteinase-2 in the periodontal ligament of the rat incisor without altering the eruption process.

PubMed

Gomes, J R; Omar, N F; Neves, J D S; Novaes, P D

2017-06-01

Doxycycline is an antibiotic agent that inhibits the activity of matrix metalloproteinases (MMPs) present in the extracellular matrix. In this study, the rat incisor was submitted to a hypofunctional condition, and the effects of doxycycline (80 mg/kg/d) on the expression and activity of MMP-2, as well as on eruption rate, were determined in the odontogenic region and in the periodontal ligament for 14 d. Rats were distributed into four groups: normofunctional (NF); doxycyline normofunctional (DNF); hypofunctional (HP); and doxycyline hypofunctional (DHP). The left lower incisors of 10 rats were shortened every 2 d, using a high-rotation drill, to produce the HP and DHP groups, after starting doxycycline treatment (80 mg/kg) by gavage. Eruption was measured using a millimeter ocular, from the gingival margin to the top of the tooth in the HP and DHP groups, and also by a mark made in the tooth previously, in the NF and DNF groups. The hemimandibles were removed and the teeth were extracted to collect the periodontal and odontogenic tissues for immunohistochemical analyses and zymography. The eruption rates were higher in the HP and the DHP groups than in the NF and DNF groups, respectively (p < 0.05). In the odontogenic region, neither of the treatments changed the expression and activity of MMP-2. In the HP group, the shortening treatment decreased the expression, but not the activity, of MMP-2, while doxycycline was able to inhibit the increase of expression and activity of MMP-2. We conclude that the inhibition of MMP-2 by doxycycline, during incisor shortening, was not enough to alter the eruption rate, which suggests that MMP-2 may have an important role in the turnover of extracellular matrix of the periodontal ligament during the tooth-eruption process. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Spectroscopic investigation of the pH controlled inclusion of doxycycline and oxytetracycline antibiotics in cationic micelles and their magnesium driven release.

PubMed

Cesaretti, Alessio; Carlotti, Benedetta; Gentili, Pier Luigi; Clementi, Catia; Germani, Raimondo; Elisei, Fausto

2014-07-24

This work presents a steady-state and time-resolved UV-visible spectroscopic investigation of two antibiotics belonging to the family of tetracyclines (doxycycline and oxytetracycline) in the micellar medium provided by p-dodecyloxybenzyltrimethylammonium bromide (pDoTABr). The spectroscopic analysis has been performed in absorption and emission with femtosecond time resolution, and at pH 5.0 and 8.7 where doxycycline and oxytetracycline are present in their neutral-zwitterionic and monoanionic forms, respectively. The experimental data have been processed by sophisticated data mining methods such as global/target analysis and the maximum entropy method. The results unambiguously indicate that, when doxycycline and oxytetracycline are in their zwitterionic form, they are entrapped within the micelle, while when they are in their monoanionic form, they preferentially show a strong one-to-one interaction with the positively charged surfactant heads. Thus, the pH of the solution controls the inclusion of the investigated drugs into the micelle. When the drugs are entrapped inside the micelles, their spectroscopic and dynamical properties after photoexcitation change appreciably. Interestingly, the entrapped drugs are still able to strongly bind Mg(2+) cations, crucial in determining the biological functioning of tetracyclines. The femtosecond resolved measurements reveal that the drugs are efficiently pulled out of the micelles by Mg(2+). In fact, magnesium-tetracycline complexes are detected in the aqueous phase. The present study suggests the potential promising use of ammonium surfactant micelles embedding doxycycline and oxytetracycline as "smart" drug delivery systems allowing their pH controlled inclusion and Mg(2+) induced release.

On the prescribing of oral doxycycline or minocycline by UK optometrists as part of management of chronic Meibomian Gland Dysfunction (MGD).

PubMed

Doughty, Michael J

2016-02-01

To review the special pharmacology of tetracycline antibiotics as anti-inflammatory drugs for treatment of obstructive Meibomian gland disease (MGD) METHODS: PubMed was used as principal resource for articles, regardless of language, on doxycycline and minocycline with key interests being on their serum and tissue pharmacokinetics and their use in clinical studies as part of management of MGD. With oral dosing of between 50 and 200mg, peak blood levels of these antibiotics have been reported to be predictably dose-dependent at between 1 and 5 microgram/mL, with human tear film levels not being detectable with 100mg dosing of doxycycline but levels of 0.2 microgram/mL with 200mg minocycline. That these two tetracycline antibiotics reach the conjunctiva is indicated by conjunctival pigmentary changes due to photosensitization after very long term use. Based the reported use in a range of clinical studies on MGD, dosing with these two antibiotics for MGD is likely to be useful at relatively low doses (e.g. 100mg for doxycycline or 50mg for minocycline, either at once or twice daily depending on severity at presentation and previous history) continued for 2 to 3 months, with the expected outcome being small-to-substantial decreases in abnormal appearance of the glands (from -4 to -89%) and increases in tear film stability (from 21 to 273%). Oral doxycycline and minocycline have predictable pharmacokinetics and have been reported to improve Meibomian gland dysfunction over a few months of use. Copyright © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Application of novel metal organic framework, MIL-53(Fe) and its magnetic hybrid: For removal of pharmaceutical pollutant, doxycycline from aqueous solutions.

PubMed

Naeimi, Shakiba; Faghihian, Hossein

2017-07-01

As a pharmaceutical pollutant, doxycycline causes contamination when enters into the environment. In this research MIL-53(Fe), and its magnetic hybrid MIL-53(Fe)/Fe 3 O 4 were synthesized and employed for removal of doxycycline from aqueous solutions. The adsorbents were characterized by XRD, SEM, BET, FTIR, EDAX, VSM and TG-DTG technique. The effect of different variables such as DOC concentration, pH, contacting time, and adsorbent dose on the removal efficiency was studied and under optimized conditions the adsorption capacity of 322mgg -1 was obtained. The adsorption process was kinetically fast and the equilibration was attained within 30min. The used adsorbent was easily separated from the solution by applying external magnetic field. The regenerated adsorbent retained most of its initial capacity after six regeneration steps. The effect of ionic strength was studied and it was indicated that removal of doxycycline from salt-containing water with moderate ionic strengths was quite feasible. Langmuir, Freundlich, Tempkin and Dubinin-Redushkevich isotherms were employed to describe the nature of adsorption process. The sorption data was well interpreted by the Longmuir model. Copyright © 2017 Elsevier B.V. All rights reserved.

Short Communication - Study on quality and efficacy of commercial tylosin and doxycycline products against local isolates of mycoplasma in broilers.

PubMed

Riazuddin, -; Khan, Sarzamin; Imtiaz, Naila; Aslam, Saima; Ahmad, Shakoor; Khan, Hamayun; Rabbani, Masood; Muhammad, Javed; Tanveer, Zafar Iqbal; Ali, Sakhawat

2017-03-01

The present study was conducted to investigate the quality and efficacy of commercially available preparations of tylosin and doxycycline available in the local market at Peshawar for poultry. In vitro and in vivo, tests were conducted to check the quality of these antimicrobial drugs. In vitro quality control test was performed by High performance liquid chromatographic (HPLC) and micro dilution method. In vivo, efficacy of the test drugs was checked in broilers infected with Mycoplasma gallisepticum. Results of HPLC indicated that test drug-2 contains doxycycline hydrochloride within specified limits but contain high quantity of active ingredient (Tylosin tartrate 120%). Recovery percentage of test drugs (3, 4, 5) were below the pharmacopoeial limit, which contained low quantity of tylosin tartrate (85%, 87.5%, 85%) respectively however, percent recovery of doxycycline were in the appropriate limits. All the tested drugs were effective against Mycoplasma gallisepticum and showed minimum inhibitory concentration (MIC) at 1.9μg/ml. The in vivo result indicated that all tested drugs decreased morbidity and mortality in infected chicks. The birds treated with test drugs (3 and 5) showed mortality of 9.5%, which was slightly higher than the other test groups. The current study suggested that there are incidences of substandard drugs in Pakistan and the drug regularity authorities should take strict actions against the manufacturing companies.

Facile synthesis of Cu(II) impregnated biochar with enhanced adsorption activity for the removal of doxycycline hydrochloride from water.

PubMed

Liu, Su; Xu, Wei-Hua; Liu, Yun-Guo; Tan, Xiao-Fei; Zeng, Guang-Ming; Li, Xin; Liang, Jie; Zhou, Zan; Yan, Zhi-Li; Cai, Xiao-Xi

2017-08-15

In this study, the effect factors and mechanisms of doxycycline hydrochloride (DOX) adsorption on copper nitrate modified biochar (Cu-BC) was investigated. Cu-BC absorbent was synthesized through calcination of peanut shells biomass at 450°C and then impregnation with copper nitrate. The Cu-BC has exhibited excellent sorption efficiency about 93.22% of doxycycline hydrochloride from aqueous solution, which was double higher than that of the unmodified biochar. The experimental results suggest that the adsorption efficiency of DOX on the Cu-BC is dominated by the strong complexation, electrostatic interactions between DOX molecules and the Cu-BC samples. Comprehensively considering the cost, efficiency and the application to realistic water, the Cu-BC hold the significant potential for enhancing the effectiveness to remove DOX from water. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of a single-dose vectored thermal pulsation procedure with a 3-month course of daily oral doxycycline for moderate-to-severe meibomian gland dysfunction.

PubMed

Hagen, Kerry B; Bedi, Raman; Blackie, Caroline A; Christenson-Akagi, Kellie J

2018-01-01

The aim of this study was to compare the efficacy of a single bilateral 12-minute vectored thermal pulsation (VTP) procedure versus daily oral doxycycline for 3 months for moderate-to-severe meibomian gland dysfunction (MGD). This prospective, randomized, parallel-group, single-masked study included 28 subjects who received either a single-dose VTP or 3 months of doxycycline treatment. At baseline and 3 months post treatment, all subjects were evaluated for the following: dry eye symptoms with a standard dry eye questionnaire (the Standard Patient Evaluation for Eye Dryness [SPEED]), meibomian gland (MG) function by counting the number of glands yielding liquid secretion with the MG evaluator (MGE), tear breakup time (TBUT) and corneal and conjunctival staining. In the VTP group, at 3 months, there was a significant improvement in MG function (4.00±1.47 to 7.73±5.53), SPEED score (11.00±3.30 to 5.42±2.15), TBUT (6.26±2.01 to 8.44±1.81), corneal staining (0.38±0.50 to 0.12±0.33) and conjunctival staining (1.69±1.93 to 0.62±0.85). In the doxycycline group, there was a significant improvement in MG function (4.63±1.41 to 10.63±5.91), SPEED score (13.42±4.17 to 9.42±5.47) and conjunctival staining (2.38±1.88 to 1.13±1.51), but the improvement in TBUT (6.90±2.56 to 7.59±2.03) and corneal staining (0.21±0.41 to 0.13±0.34) was not statistically significant ( p =0.262 and p =0.414, respectively). At 3 months, SPEED score was significantly better in the VTP group ( p <0.05); other parameters were comparable between the two groups. A single 12-minute bilateral VTP procedure was significantly more effective than the 3-month daily course of oral doxycycline at improving the dry eye symptoms secondary to MGD. A single 12-minute VTP treatment was at least as effective as a dose of doxycycline for 3 months, in improving MG function and all measured signs of MGD. Given the minimal risk profile of the single VTP procedure over long-term doxycycline use, a single

Doxycycline Inducible Melanogenic Vaccinia Virus as Theranostic Anti-Cancer Agent.

PubMed

Kirscher, Lorenz; Deán-Ben, Xosé Luis; Scadeng, Miriam; Zaremba, Angelika; Zhang, Qian; Kober, Christina; Fehm, Thomas Felix; Razansky, Daniel; Ntziachristos, Vasilis; Stritzker, Jochen; Szalay, Aladar A

2015-01-01

We reported earlier the diagnostic potential of a melanogenic vaccinia virus based system in magnetic resonance (MRI) and optoacoustic deep tissue imaging (MSOT). Since melanin overproduction lead to attenuated virus replication, we constructed a novel recombinant vaccinia virus strain (rVACV), GLV-1h462, which expressed the key enzyme of melanogenesis (tyrosinase) under the control of an inducible promoter-system. In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models. Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography. At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.

Inhibition of ADAMTS-13 by Doxycycline Reduces von Willebrand Factor Degradation During Supraphysiological Shear Stress: Therapeutic Implications for Left Ventricular Assist Device-Associated Bleeding.

PubMed

Bartoli, Carlo R; Kang, Jooeun; Restle, David J; Zhang, David M; Shabahang, Cameron; Acker, Michael A; Atluri, Pavan

2015-11-01

The aim of this study was to investigate a potential therapy for left ventricular assist device (LVAD)-associated bleeding. Nonsurgical bleeding is the most frequent complication of LVAD support. Recent evidence has demonstrated that supraphysiological shear stress from continuous-flow LVADs accelerates von Willebrand factor (vWF) metabolism by the action of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) (the vWF protease). An acquired vWF deficiency causes bleeding. This suggests that ADAMTS-13 is a clinical target to reduce vWF degradation. We tested the hypothesis that inhibition of ADAMTS-13 with doxycycline, an inexpensive, clinically approved drug, reduces vWF degradation during shear stress. Whole blood was collected from human donors (n = 15), and purified, recombinant ADAMTS-13 protein was obtained. An enzyme-linked immunosorbent assay (ELISA) was used to quantify the dose relationship between doxycycline and ADAMTS-13 activity prior to shear stress (n = 10). To determine the effect of shear stress, plasma and recombinant ADAMTS-13 were exposed to LVAD-like supraphysiological shear stress (approximately 175 dyne/cm(2)). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting (n = 10). Förster resonance energy transfer was used to quantify plasma ADAMTS-13 activity (n = 10). An ELISA was used to quantify vWF:collagen binding activity. Platelet aggregometry was performed with adenosine 5'-diphosphate, collagen, and ristocetin (vWF-platelet pathway) agonism (n = 10). Doxycycline significantly decreased plasma ADAMTS-13 activity (p = 0.01) and the activity of recombinant human ADAMTS-13 protein by 21%. After plasma was exposed to shear stress, the same pattern of vWF degradation was observed as previously reported for LVAD patients, and vWF:collagen binding activity decreased significantly (p = 0.002). Doxycycline significantly decreased ADAMTS-13 activity (p = 0.04) and

Construction of Nef-positive doxycycline-dependent HIV-1 variants using bicistronic expression elements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Velden, Yme U. van der; Kleibeuker, Wendy; Harwig, Alex

Conditionally replicating HIV-1 variants that can be switched on and off at will are attractive tools for HIV research. We previously developed a genetically modified HIV-1 variant that replicates exclusively when doxycycline (dox) is administered. The nef gene in this HIV-rtTA variant was replaced with the gene encoding the dox-dependent rtTA transcriptional activator. Because loss of Nef expression compromises virus replication in primary cells and precludes studies on Nef function, we tested different approaches to restore Nef production in HIV-rtTA. Strategies that involved translation via an EMCV or synthetic internal ribosome entry site (IRES) failed because these elements were incompatiblemore » with efficient virus replication. Fusion protein approaches with the FMDV 2A peptide and human ubiquitin were successful and resulted in genetically-stable Nef-expressing HIV-rtTA strains that replicate more efficiently in primary T-cells and human immune system (HIS) mice than Nef-deficient variants, thus confirming the positive effect of Nef on in vivo virus replication. - Highlights: • Different approaches to encode additional proteins in the HIV-1 genome were tested. • IRES translation elements are incompatible with efficient HIV-1 replication. • Ubiquitin and 2A fusion protein approaches allow efficient HIV-1 replication. • Doxycycline-controlled HIV-1 variants that encode all viral proteins were developed. • Nef stimulates HIV-rtTA replication in primary cells and human immune system mice.« less

Doxycycline treatment in dialysis related amyloidosis: discrepancy between antalgic effect and inflammation, studied with FDG-positron emission tomography: a case report.

PubMed

Piccoli, Giorgina Barbara; Hachemi, Mammar; Molfino, Ida; Coindre, Jean Philippe; Boursot, Charles

2017-09-06

No effective treatment is currently available and dialysis related amyloidosis continues to be invalidating in long-term dialysis patients. A recent case series reported reduction of osteoarticular pain on doxycycline treatment, extending the indications of this drug, used in other uncommon forms of amyloidosis, to dialysis patients. Explanations of the antalgic effect were the anti-inflammatory properties and anti-coiling effects of tetracycline. Our report regards a 54-year-old woman, who was never transplanted and has been on hemodialysis and hemodiafiltration for overall 37 years, due to renal hypoplasia. In spite of high efficiency hemodiafiltration, she complained of increasing, invalidating osteoarticular pain; history and imaging suggested beta-2 microglobulin amyloid. Positron emission tomography (PET scan) identified metabolically active lesions in the involved settings. Low-dose doxycycline (100 mg/day) was started, leading to a considerable decrease in pain (over 6 months, from 7 to 8 to 4-5 on a 0-10 scale). At 6 months, a PET scan showed unmodified or increased uptake in the involved settings. In summary, the previously described antalgic effect of doxycycline in dialysis related amyloidosis is confirmed in our case, the first studied using PET scan. The pattern at PET can suggests that the antalgic effect is independent from inflammation and points to other factors, such as interaction with fibril geometry or with bone structure.

The efficacy of ranitidine bismuth citrate, amoxicillin and doxycycline or tetracycline regimens as a first line treatment for Helicobacter pylori eradication.

PubMed

Akyildiz, Murat; Akay, Sinan; Musoglu, Ahmet; Tuncyurek, Muge; Aydin, Ahmet

2009-01-01

The eradication rates of Helicobacter pylori (H. pylori) clearly decreased with standard PPI-based triple therapies. To assess the efficacy of two different triple therapies consisting of ranitidine bismuth citrate-amoxicillin-doxycycline and ranitidine bismuth citrate-amoxicillin-tetracycline combinations as a first line treatment option. One hundred and fifteen consecutive dyspeptic patients in whom H. pylori infection was diagnosed for the first time were enrolled in this study. The patients were randomized into two groups. Group 1 (n=57) was assigned to receive a 14-day triple therapy consisting of ranitidine bismuth citrate 400 mg (b.i.d.), amoxicillin 1 g (b.i.d) and doxycycline 100 mg (b.i.d.). Group 2 (n=58) was assigned to receive a 14-day triple therapy consisting of ranitidine bismuth citrate 400 mg (b.i.d.), amoxicillin 1 g (b.i.d.) and tetracycline 500 mg (q.i.d.). The eradication was achieved in 45.7% (21/46) and 40.8% (20/49) of the patients in group 1 and group 2, according to per protocol analysis. The intention-to-treat eradication rates were 36.8% (21/57) and 34.5% (20/58) in group 1 and group 2, respectively. Two-week therapy with neither ranitidine bismuth citrate-amoxicillin-doxycycline nor ranitidine bismuth citrate-amoxicillin-tetracycline is adequately effective for H. pylori eradication as a first line therapy.

Peripheral nerve pathology, including aberrant Schwann cell differentiation, is ameliorated by doxycycline in a laminin-α2-deficient mouse model of congenital muscular dystrophy

PubMed Central

Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey Boone

2011-01-01

The most common form of childhood congenital muscular dystrophy, Type 1A (MDC1A), is caused by mutations in the human LAMA2 gene that encodes the laminin-α2 subunit. In addition to skeletal muscle deficits, MDC1A patients typically show a loss of peripheral nerve function. To identify the mechanisms underlying this loss of nerve function, we have examined pathology and cell differentiation in sciatic nerves and ventral roots of the laminin-α2-deficient (Lama2−/−) mice, which are models for MDC1A. We found that, compared with wild-type, sciatic nerves of Lama2−/− mice had a significant increase in both proliferating (Ki67+) cells and premyelinating (Oct6+) Schwann cells, but also had a significant decrease in both immature/non-myelinating [glial fibrillary acidic protein (GFAP)+] and myelinating (Krox20+) Schwann cells. To extend our previous work in which we found that doxycycline, which has multiple effects on mammalian cells, improves motor behavior and more than doubles the median life-span of Lama2−/− mice, we also determined how nerve pathology was affected by doxycycline treatment. We found that myelinating (Krox20+) Schwann cells were significantly increased in doxycycline-treated compared with untreated sciatic nerves. In addition, doxycycline-treated peripheral nerves had significantly less pathology as measured by assays such as amount of unmyelinated or disorganized axons. This study thus identified aberrant proliferation and differentiation of Schwann cells as key components of pathogenesis in peripheral nerves and provided proof-of-concept that pharmaceutical therapy can be of potential benefit for peripheral nerve dysfunction in MDC1A. PMID:21505075

Minocycline and doxycycline, but not other tetracycline-derived compounds, protect liver cells from chemical hypoxia and ischemia/reperfusion injury by inhibition of the mitochondrial calcium uniporter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwartz, Justin; Holmuhamedov, Ekhson; Zhang, Xun

Minocycline, a tetracycline-derived compound, mitigates damage caused by ischemia/reperfusion (I/R) injury. Here, 19 tetracycline-derived compounds were screened in comparison to minocycline for their ability to protect hepatocytes against damage from chemical hypoxia and I/R injury. Cultured rat hepatocytes were incubated with 50 μM of each tetracycline-derived compound 20 min prior to exposure to 500 μM iodoacetic acid plus 1 mM KCN (chemical hypoxia). In other experiments, hepatocytes were incubated in anoxic Krebs–Ringer–HEPES buffer at pH 6.2 for 4 h prior to reoxygenation at pH 7.4 (simulated I/R). Tetracycline-derived compounds were added 20 min prior to reperfusion. Ca{sup 2+} uptake wasmore » measured in isolated rat liver mitochondria incubated with Fluo-5N. Cell killing after 120 min of chemical hypoxia measured by propidium iodide (PI) fluorometry was 87%, which decreased to 28% and 42% with minocycline and doxycycline, respectively. After I/R, cell killing at 120 min decreased from 79% with vehicle to 43% and 49% with minocycline and doxycycline. No other tested compound decreased killing. Minocycline and doxycycline also inhibited mitochondrial Ca{sup 2+} uptake and suppressed the Ca{sup 2+}-induced mitochondrial permeability transition (MPT), the penultimate cause of cell death in reperfusion injury. Ru360, a specific inhibitor of the mitochondrial calcium uniporter (MCU), also decreased cell killing after hypoxia and I/R and blocked mitochondrial Ca{sup 2+} uptake and the MPT. Other proposed mechanisms, including mitochondrial depolarization and matrix metalloprotease inhibition, could not account for cytoprotection. Taken together, these results indicate that minocycline and doxycycline are cytoprotective by way of inhibition of MCU. - Highlights: • Minocycline and doxycycline are the only cytoprotective tetracyclines of those tested • Cytoprotective tetracyclines inhibit the MPT and mitochondrial calcium and iron uptake. �

Multidrug-resistant Neisseria gonorrhoeae failing treatment with ceftriaxone and doxycycline in France, November 2017.

PubMed

Poncin, Thibault; Fouere, Sebastien; Braille, Aymeric; Camelena, Francois; Agsous, Myriem; Bebear, Cecile; Kumanski, Sylvain; Lot, Florence; Mercier-Delarue, Severine; Ngangro, Ndeindo Ndeikoundam; Salmona, Maud; Schnepf, Nathalie; Timsit, Julie; Unemo, Magnus; Bercot, Beatrice

2018-05-01

We report a multidrug-resistant Neisseria gonorrhoeae urogenital and pharyngeal infection with ceftriaxone resistance and intermediate resistance to azithromycin in a heterosexual woman in her 20s in France. Treatment with ceftriaxone plus doxycycline failed for the pharyngeal localisation. Whole-genome sequencing of isolate F90 identified MLST 1903 , NG-MAST ST 3435 , NG-STAR 233 , and relevant resistance determinants. F90 showed phenotypic and genotypic similarities to an internationally spreading multidrug-resistant and ceftriaxone-resistant clone detected in Japan and subsequently in Australia, Canada and Denmark.

Piroxicam and doxycycline treatment for an oral squamous cell carcinoma in an inshore bottlenose dolphin (Tursiops aduncus).

PubMed

March, D T; Blyde, D J; Bossart, G D; Begg, A P; Taylor, D P; McClure, V

2016-06-01

The virus family Papillomaviridae has been documented in a wide range of animal species and can cause benign and malignant proliferative lesions. The presence of concurrent lingual papillomas and squamous cell carcinomas (SCC) in cetaceans has also been documented in both wild and captive populations, suggesting malignant transformation of benign papilloma to SCC may occur in this species. In 2008, a 38-year-old captive male inshore bottlenose dolphin (Tursiops aduncus) was diagnosed with papillomatous lesions on the intermandibular frenulum rostral to the tongue and an infiltrative SCC of the soft palate following biopsy and histological analysis. A treatment regimen of piroxicam and doxycycline was initiated with misoprostol as a gastroprotectant. The treatment resulted in a marked reduction in tumour size and reversible hepatotoxicosis. Subsequent biopsies revealed the presence of SCC in the oral cavity; however, the disease remains stable at the time of writing. To the best of our knowledge, this case is the first report of piroxicam and doxycycline used to treat SCC in a bottlenose dolphin. The treatment was successful in reducing the clinical presentation of the disease. © 2016 Australian Veterinary Association.

Lyme carditis with isolated left bundle branch block and myocarditis successfully treated with oral doxycycline.

PubMed

Cunha, Burke A; Elyasi, Maekal; Singh, Prince; Jimada, Ismail

2018-01-01

Lyme disease may present with a variety of cardiac manifestations ranging from first degree to third degree heart block. Cardiac involvement with Lyme disease may be asymptomatic, or symptomatic. Atrioventrical conduction abnormalities are the most common manifestation of Lyme carditis. Less common, are alternating right bundle branch block (RBBB) and left bundle branch block (LBBB). We present an interesting case of a young male whose main manifestation of Lyme carditis was isolated LBBB. He also had mild Lyme myocarditis. The patient was successfully treated with oral doxycycline, and his isolated LBBB and myocarditis rapidly resolved.

Synthesis and Characterization of Photoactivatable Doxycycline Analogues Bearing Two-Photon-Sensitive Photoremovable Groups Suitable for Light-Induced Gene Expression.

PubMed

Goegan, Bastien; Terzi, Firat; Bolze, Frédéric; Cambridge, Sidney; Specht, Alexandre

2018-06-18

We report the synthesis and photolytic properties of caged 9-aminodoxycycline derivatives modified with 2-{4'-bis-[2-(2methoxyethoxy)ethyl]-4-nitrobiphenyl-3-yl}prop-1-oxy (EANBP) and PEG7-ylated (7-diethylamino-2-oxo-2H-chromen-4-yl)methyl (PEG7-DEACM) groups. 9-Aminodoxycycline is a tetracycline analogue capable of activating transcription through the inducible TetOn transgene expression system and can be regioselectively coupled to two-photon-sensitive photo-removable protecting groups by carbamoylation. The EANBP-based caged 9-aminodoxycycline showed complex photochemical reactions but did release 10 % of 9-aminodoxycycline. However, 9-(PEG7-DEACMamino)doxycycline exhibited excellent photolysis efficiency at 405 nm with quantitative release of 9-aminodoxycycline and a 0.21 uncaging quantum yield. Thanks to the good two-photon sensitivity of the DEACM chromophore, 9-aminodoxycycline release by two-photon photolysis is possible, with calculated action cross-sections of up to 4.0 GM at 740 nm. Therefore, 9-(PEG7-DEACMamino)doxycycline represents a very attractive tool for the development of a light-induced gene expression method in living cells. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: development, in-vitro and in-vivo clinical evaluation.

PubMed

Gad, Heba A; Kamel, Amany O; Ezzat, Ola M; El Dessouky, Hadir F; Sammour, Omaima A

2017-11-01

To formulate solid lipid microparticles (SLMs) encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) for the treatment of periodontal diseases. SLMs were prepared applying hot homogenization method, using different types of lipids and stabilized with various types and concentrations of surfactants. The optimized formula was subjected to freeze-drying followed by incorporation into poloxamer gel. Microbiological and clinical evaluation of the selected SLMs on patients suffering from periodontal diseases was performed. SLMs could entrap high percentage of both drugs (81.14% and 68.75 % for doxycycline hydrochloride and metronidazole respectively). Transmission electron microscopy images of SLMs showed nearly spherical particles. Freeze-dried SLMs showed satisfactory stability for three months. Combined drugs were molecularly dispersed in SLMs. Incorporation of the freeze-dried SLMs powder in poloxamer gel could control the drugs release for 72 h. In-vivo study revealed effective and safe use of SLMs gel for periodontitis treatment. Significant improvement in both microbiological and clinical parameters was observed as compared to scaling and root planing alone. The formulated SLMs gel offers an applicable dosage form that can be injected directly into the periodontal pocket as adjunctive to scaling and root planing.

Successful treatment of Miescher's cheilitis in Melkersson-Rosenthal syndrome with betamethasone injections and doxycycline

PubMed Central

Oudrhiri, Lamia; Chiheb, Soumiya; Marnissi, Farida; Zamiati, Soumaya; Benchikhi, Hakima

2012-01-01

We report a case of a 19-year-old girl who presented with 5-year history of swelling of upper lip and fissured tongue treated with dapsone then oral steroids without any improvement. Clinical examination found peripheral facial nerve paralysis and Labial mucosa biopsy showed non-necrotizing giganto-epithelioid granuloma. Diagnosis of Melkersson-Rosenthal syndrome was retaind because of association of cheilitis, lingua plicata and facial paralysis. Given the failure of dapsone and oral steroid we suggested an association of betamethasone injection and doxycycline. Gradual and permanent reduction of the upper lip volume was observed. One year follow up objectified no reactivation of cheilitis. PMID:23397029

Sub-antimicrobial Doxycycline for Periodontitis Reduces Hemoglobin A1c in Subjects with Type 2 Diabetes: a Pilot Study

PubMed Central

Engebretson, Steven P.; Hey-Hadavi, Judith

2011-01-01

In vitro and animal studies suggest a possible role for the tetracycline class of drugs in the inhibition of non-enzymatic protein glycation. We conducted a 3-month, randomized placebo-controlled pilot clinical trial of conventional sub-gingival debridement, (periodontal therapy) combined with either a three month regimen of sub-antimicrobial-dose doxycycline (SDD), a two week regimen of antimicrobial-dose doxycycline (ADD), or placebo in 45 patients with long-standing type 2 diabetes (mean duration 9 years) and untreated chronic periodontitis. Subjects were taking stable doses of oral hypoglycemic medications and/or insulin. Treatment response was assessed by measuring hemoglobin A1c (HbA1c),plasma glucose, and clinical periodontal disease measures. At one-month and three-month follow-up, clinical measures of periodontitis were decreased in all groups(data to be presented elsewhere). At three months, mean HbA1c levels in the SDD group were reduced 0.9% unitsfrom 7.2% units ± 2.2(±SD), to 6.3% units ±1.1, which represents a 12.5% improvement. In contrast, there was no significant change in HbA1c in the ADD (7.5%± 2.0 to 7.8%± 2.1) or placebo (8.5%± 2.0 to 8.5%± 2.6) groups. Mean HbA1c change from baseline was significantly greater in the SDD group compared with the ADD group (p=0.04) but not placebo (p=0.22). Moreover, a larger proportion of subjects in the SDD group experienced improvement (p<0.05) compared to the ADD or placebo groups. Mean plasma glucose levels were not significantly different between or within the groups. The results of this pilot study suggest that the treatment of periodontitis with sub-gingival debridement and 3-months of daily sub-antimicrobial-dose doxycycline may decrease HbA1c in patients with type 2 diabetes taking normally prescribed hypoglycemic agents. PMID:21782948

Comparative randomized pilot study of azithromycin and doxycycline efficacy and tolerability in the treatment of prostate infection caused by Ureaplasma urealyticum.

PubMed

Skerk, Visnja; Mareković, Ivana; Markovinović, Leo; Begovac, Josip; Skerk, Vedrana; Barsić, Neven; Majdak-Gluhinić, Vida

2006-01-01

A total of 1,442 patients with symptoms of chronic prostatitis were examined over a 4-year period at the Outpatient Department for Urogenital Infections, University Hospital for Infectious Diseases Dr. Fran Mihaljević, Zagreb, Croatia. The inclusion criteria for chronic prostatitis caused by Ureaplasma urealyticum were the presence of clinical symptoms, presence of U. urealyticum in expressed prostatic secretion (EPS) or voided urine collected immediately after prostatic massage (VB(3)), absence of U. urealyticum in urethral swabs and absence of other possible pathogens of chronic prostatitis in EPS or VB(3). A total of 63 patients with prostate infection caused by U. urealyticum were available for this pilot study. The patients were randomized according to a computer randomization list to receive a total dose of 4.5 g of azithromycin given as a 3-day therapy of 1 x 500 mg weekly for 3 weeks or doxycyline 100 mg b.i.d. for 21 days. Patients' sexual partners were treated at the same time. Clinical efficacy and tolerability of the administered drug as well as possible adverse events were evaluated during, at the end and 4-6 weeks after completion of therapy. Bacteriological efficacy was evaluated 4-6 weeks after completion of therapy. Treatment groups did not differ regarding age, distribution of urethral, prostatic, sexual and other symptoms, or digitorectal prostatic examination. Five patients treated with doxycycline had nausea. In the group of patients with prostate infection caused by U. urealyticum, the eradication rate was not significantly different with regard to the administered azithromycin (25/32) or doxycycline (23/31). Clinical cure did not significantly differ with regard to the administered azithromycin (22/32) or doxycycline (21/31). Copyright 2006 S. Karger AG, Basel.

Influence of mycotoxin binders on the oral bioavailability of tylosin, doxycycline, diclazuril, and salinomycin in fed broiler chickens.

PubMed

De Mil, T; Devreese, M; Maes, A; De Saeger, S; De Backer, P; Croubels, S

2017-07-01

The presence of mycotoxins in broiler feed can have deleterious effects on the wellbeing of the animals and their performance. Mycotoxin binders are feed additives that aim to adsorb mycotoxins in the intestinal tract and thereby prevent the oral absorption of the mycotoxin. The simultaneous administration of coccidiostats and/or antimicrobials with mycotoxin binders might lead to a reduced oral bioavailability of these veterinary medicinal products. This paper describes the influence of 3 mycotoxin binders (i.e., clay 1 containing montmorillonite, mica, and feldspars; clay 2 containing montmorillonite and quartz; and yeast 1 being a modified glucomannan fraction of inactivated yeast cells) and activated carbon on the oral bioavailability and pharmacokinetic parameters of the antimicrobials doxycycline and tylosin, and the coccidiostats diclazuril and salinomycin. A feeding study with 40 15 day-old broilers was performed evaluating the effects of long-term feeding 2 g mycotoxin binder/kg of feed. The birds were randomly divided into 5 groups of 8 birds each, i.e., a control group receiving no binder and 4 test groups receiving either clay 1, clay 2, yeast 1, or activated carbon mixed in the feed. After 15 d of feeding, both the control and each test group were administered doxycycline, tylosin, diclazuril, and salinomycin, consecutively, respecting a wash-out period of 2 to 3 d between each administration. The 4 medicinal products were dosed using a single bolus administration directly in the crop. After each bolus administration, blood was collected for plasma analysis and calculation of the main pharmacokinetic parameters and relative oral bioavailability (F = area under the plasma concentration-time curve (AUC0-8 h) in the test groups/AUC0-8 h in the control group)*100). No effects were observed of any of the mycotoxin binders on the relative oral bioavailability of the coccidiostats (i.e., F between 82 and 101% and 79 and 93% for diclazuril and salinomycin

A randomised controlled trial to compare the safety, effectiveness and cost-effectiveness of doxycycline (200 mg/day) with that of oral prednisolone (0.5 mg/kg/day) for initial treatment of bullous pemphigoid: the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial.

PubMed

Chalmers, Joanne R; Wojnarowska, Fenella; Kirtschig, Gudula; Mason, James; Childs, Margaret; Whitham, Diane; Harman, Karen; Chapman, Anna; Walton, Shernaz; Schmidt, Enno; Godec, Thomas R; Nunn, Andrew J; Williams, Hywel C

2017-03-01

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder with increased morbidity and mortality in the elderly. To evaluate the effectiveness, safety and cost-effectiveness of a strategy of initiating BP treatment with oral doxycycline or oral prednisolone. We hypothesised that starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral prednisolone. Pragmatic multicentre two-armed parallel-group randomised controlled trial with an economic evaluation. A total of 54 dermatology secondary care centres in the UK and seven in Germany. Adults with BP [three or more blisters at two sites and positive direct and/or indirect immunofluorescence (immunoglobulin G and/or complement component 3 immunofluorescence at the dermal-epidermal junction)] and able to give informed consent. Participants were allocated using online randomisation to initial doxycycline treatment (200 mg/day) or prednisolone (0.5 mg/kg/day). Up to 30 g/week of potent topical corticosteroids was permitted for weeks 1-3. After 6 weeks, clinicians could switch treatments or alter the prednisolone dose as per normal practice. Primary outcomes: (1) the proportion of participants with three or fewer blisters at 6 weeks (investigator blinded) and (2) the proportion with severe, life-threatening and fatal treatment-related events at 52 weeks. A regression model was used in the analysis adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Secondary outcomes included the effectiveness of blister control after 6 weeks, relapses, related adverse events and quality of life. The economic evaluation involved bivariate regression of costs and quality-adjusted life-years (QALYs) from a NHS perspective. In total, 132 patients were randomised to doxycycline and 121 to prednisolone. The mean patient age was 77.7 years and baseline severity was as follows: mild 31.6% (three

The influence of cooking procedures on doxycycline concentration in contaminated eggs.

PubMed

Gajda, Anna; Bladek, Tomasz; Gbylik-Sikorska, Malgorzata; Posyniak, Andrzej

2017-04-15

Doxycycline (DC) is forbidden compound in laying hens. Most information about drug residues in eggs concern their concentrations in raw matrix and the data about the influence of cooking on antibiotics residues in eggs are limited. Thus, the residues concentration of DC in eggs after different cooking methods was investigated. Analyses of DC were assayed by liquid chromatography - tandem mass spectrometry method. The stability of DC in eggs were depended upon the type and time of cooking procedure. By microwaving DC was reduced most effective with concentrations decreased by 53% and 50.3% after 4min of microwaving without cover and microwaving with cover, respectively. In fried eggs, DC was reduced by 39.8% in 6min. By the boiling cooking, the smallest reduction was observed with the concentration decreased by 29.8% after 8min. The obtained results show that ordinary cooking does not eliminate the all DC residues present in eggs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Short communication: Interaction of the isomers carvacrol and thymol with the antibiotics doxycycline and tilmicosin: In vitro effects against pathogenic bacteria commonly found in the respiratory tract of calves.

PubMed

Kissels, W; Wu, X; Santos, R R

2017-02-01

Bovine respiratory disease is the major problem faced by cattle, specially calves, leading to reduced animal performance and increased mortality, consequently causing important economic losses. Hence, calves must be submitted to antibiotic therapy to counteract this infection usually initiated by the combination of environmental stress factors and viral infection, altering the animal's defense mechanism, and thus allowing lung colonization by the opportunistic bacteria Mannheimia haemolytica and Pasteurella multocida. Essential oils appear to be candidates to replace antibiotics or to act as antibiotic adjuvants due to their antimicrobial properties. In the present study, we aimed to evaluate the 4 essential oil components carvacrol, thymol, trans-anethole, and 1,8 cineole as antibacterial agents or as adjuvants for the antibiotics doxycycline and tilmicosin against M. haemolytica and P. multocida. Bacteria were cultured according to standard protocols, followed by the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration. A checkerboard assay was applied to detect possible interactions between components, between antibiotics, and between components and antibiotics. Doxycycline at 0.25 and 0.125 μg/mL inhibited the growth of P. multocida and M. haemolytica, respectively, whereas tilmicosin MIC values were 1.0 and 4.0 μg/mL for P. multocida and M. haemolytica, respectively. Carvacrol MIC values were 2.5 and 1.25 mM for P. multocida and M. haemolytica, respectively, whereas thymol MIC values were 1.25 and 0.625 mM for P. multocida and M. haemolytica, respectively. Trans-anethole and 1,8 cineole did not present any antibacterial effect even at 40 mM against the investigated pathogens. All minimum bactericidal concentration values were the same as MIC, except when thymol was tested against M. haemolytica, being twice the MIC data (i.e., 1.25 mM thymol). Based on fractional inhibitory concentration checkerboard assay, no

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin.

PubMed

Zhang, Nan; Ye, Xiaomei; Wu, Yuzhi; Huang, Zilong; Gu, Xiaoyan; Cai, Qinren; Shen, Xiangguang; Jiang, Hongxia; Ding, Huanzhong

2017-01-01

Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99) and the mutant prevention concentration (MPC). Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105-109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and danofloxacin had the highest rate of reduction.

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin

PubMed Central

Zhang, Nan; Ye, Xiaomei; Wu, Yuzhi; Huang, Zilong; Gu, Xiaoyan; Cai, Qinren; Shen, Xiangguang; Jiang, Hongxia; Ding, Huanzhong

2017-01-01

Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99) and the mutant prevention concentration (MPC). Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105–109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and danofloxacin had the highest rate of reduction. PMID:28052123

Influence of Mycotoxin Binders on the Oral Bioavailability of Doxycycline in Pigs.

PubMed

De Mil, Thomas; Devreese, Mathias; De Saeger, Sarah; Eeckhout, Mia; De Backer, Patrick; Croubels, Siska

2016-03-16

Mycotoxin binders are feed additives that aim to adsorb mycotoxins in the gastrointestinal tract of animals, making them unavailable for systemic absorption. The antimicrobial drug doxycycline (DOX) is often used in pigs and is administered through feed or drinking water; hence, DOX can come in contact with mycotoxin binders in the gastrointestinal tract. This paper describes the effect of four mycotoxin binders on the absorption of orally administered DOX in pigs. Two experiments were conducted: The first used a setup with bolus administration to fasted pigs at two different dosages of mycotoxin binder. In the second experiment, DOX and the binders were mixed in the feed at dosages recommended by the manufacturers (= field conditions). Interactions are possible between some of the mycotoxin binders dosed at 10 g/kg feed but not at 2 g/kg feed. When applying field conditions, no influences were seen on the plasma concentrations of DOX.

The excretion and environmental effects of amoxicillin, ciprofloxacin, and doxycycline residues in layer chicken manure.

PubMed

Peng, Ping-cai; Wang, Yan; Liu, Long-yong; Zou, Yong-de; Liao, Xin-di; Liang, Juan-boo; Wu, Yin-bao

2016-05-01

The excretion rates and ecological risk to the environment of three commonly used veterinary antibiotics (VAs), amoxicillin, ciprofloxacin, and doxycycline, in layer hen manure during the application and withdrawal periods were investigated in a study consisting of a control group fed with VA-free basal diet and nine treatment groups consisted of three levels (200 mg/kg, 100 mg/kg, and 50 mg/kg) of amoxicillin (AMX), ciprofloxacin (CIP), or doxycycline (DOC). Each treatment group was replicated seven times with three layer hens per replication. Results of the study showed that the average excretion rates of AMX in the 200, 100, and 50 mg/kg groups were 67.88, 55.82, and 66.15%, respectively, while those for CIP and DOC were 47.84, 51.85, and 44.87% and 82.67, 94.39, and 95.72%, respectively. The concentrations of the above veterinary drugs in manure decreased sharply in the withdrawal period (7, 28, and 10 d, respectively), for AMX, DOC, and CIP. Neither AMX nor DOC was detected in the manure after the withdrawal period. In contrast to AMX and DOC, the excretion rate of CIP was significantly lower and thus had a longer residence time. Ecological risk study, estimated using hazard quotient values, showed that AMX in the 100 and 50 mg/kg groups posed no risk to the environment after d 1 of withdrawal, while CIP in the 50 mg/kg group posed no risk to the environment from d 5 of withdrawal. CIP in the 200 and 100 mg/kg groups required 10 d withdrawal in order to pose no risk to the environment. In contrast, DOC residue during withdrawal in the manure posed no risk to the environment, thus making it more environmentally safe. © 2016 Poultry Science Association Inc.

Doxycycline potentiates antitumor effect of cyclophosphamide in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chhipa, Rishi Raj; Singh, Sandeep; Surve, Sachin V.

2005-02-01

Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX alsomore » potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 {mu}g/ml), the IC{sub 50} value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.« less

Assessment of parasitological findings in heartworm-infected beagles treated with Advantage Multi® for dogs (10% imidacloprid + 2.5% moxidectin) and doxycycline.

PubMed

Savadelis, Molly D; Ohmes, Cameon M; Hostetler, Joe A; Settje, Terry L; Zolynas, Robert; Dzimianski, Michael T; Moorhead, Andrew R

2017-05-19

Anecdotal reports support the position that the adulticidal heartworm treatment utilizing doxycycline and Advantage Multi®/Advocate® for Dogs (10% imidacloprid + 2.5% moxidectin) has successfully converted antigen-positive dogs to antigen-negative. To date, no controlled experimental studies have demonstrated the adulticidal efficacy of this treatment regimen. The aim of this study was to evaluate the parasitological and clinical efficacy of Advantage Multi® for Dogs (IMD + MOX) and doxycycline in heartworm-infected beagles. This study utilized 16 dogs, 8 dogs in each of non-treated control and treated groups. A total of 16 adult Dirofilaria immitis (Missouri strain) were surgically transplanted into the jugular vein of each study dog. The treatment regimen of monthly IMD + MOX topically (per labeled dosage and administration) for 10 months and 10 mg/kg doxycycline BID orally for 30 days was initiated 30 days post-surgical transplant. Echocardiograms, radiographs, complete blood counts, clinical chemistry profiles, heartworm antigenemia and microfilaremia were evaluated every 4 weeks. Serum samples were assayed for heartworm antigen using the DiroCHEK® heartworm antigen test. The DiroCHEK® was performed according to the manufacturer's recommendations and read using a spectrophotometer at 490 nm. All dogs tested positive for the presence of heartworm antigen post-surgical transplant and prior to treatment. Heartworm antigen levels began declining in treated dogs 3 months post-treatment. Non-treated control dogs remained antigen-positive. No microfilariae were detected in treated dogs after 21 days post-treatment. At necropsy, adult heartworms were recovered from all non-treated control dogs with a range of 10-12 adult worms/dog for an average recovery of 10.6 adult heartworms/dog. In the IMD + MOX- and doxycycline-treated dogs, the range of adult heartworms recovered was 0-2 adult worms/dog, with five dogs having no adult heartworms

Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways.

PubMed

Ben-Azu, Benneth; Omogbiya, Itivere Adrian; Aderibigbe, Adegbuyi Oladele; Umukoro, Solomon; Ajayi, Abayomi Mayowa; Iwalewa, Ezekiel O

2018-05-01

The involvement of oxidative, nitrergic, cholinergic and inflammatory alterations have been reported to contribute to the pathophysiology of schizophrenia, a debilitating neuropsychiatric disorder. Our previous studies have shown that doxycycline (DOX), a notable member of tetracyclines with proven antioxidant and anti-inflammatory properties, attenuated psychotic-like behaviors induced by apomophine and ketamine (KET) in mice. This present study was designed to further evaluate in detail the ability of DOX and its combination with risperidone (RIS) to prevent and reverse KET-induced schizophrenic-like behaviors and the role of oxidative/nitrergic and cholinergic pathways in mice. In the prevention protocol, mice were treated orally with DOX (25, 50 or 100 mg/kg), RIS (0.5 mg/kg), DOX (50 mg/kg) in combination with RIS, or vehicle for 14 consecutive days. In addition, the animals received intraperitoneal injection of KET (20 mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or vehicle for 14 days prior to DOX, RIS, DOX in-combination with RIS or vehicle treatments. Schizophrenic-like behaviors consisting of positive, negative and cognitive symptoms were evaluated using open field, social interaction, Y-maze and novel object recognition tests. Thereafter, the brain levels of biomarkers of oxidative stress, nitrite and acetylcholinesterase activity were determined. DOX given alone or in combination with RIS attenuated schizophrenic-like behaviors induced by chronic injection of KET in both preventive and reversal treatment protocols. DOX significantly increased glutathione, superoxide dismutase and catalase levels in the brain of chronic KET-treated mice. However, it decreased malonyladehyde, nitrite levels and acetylcholinesterase activity when given alone or in-combination with RIS in both protocols. Taken together, these findings showed that doxycycline ameliorated schizophrenic-like behaviors induced by ketamine

In vitro activities of amoxicillin-clavulanate, doxycycline, ceftazidime, imipenem, and trimethoprim-sulfamethoxazole against biofilm of Brazilian strains of Burkholderia pseudomallei.

PubMed

Bandeira, Tereza de Jesus Pinheiro Gomes; Moreira, Camila Alencar; Brilhante, Raimunda Sâmia Nogueira; Castelo-Branco, Débora de Souza Collares Maia; Neto, Manoel Paiva de Araújo; Cordeiro, Rossana de Aguiar; Rodrigues, Terezinha de Jesus Santos; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

2013-11-01

This study aimed at investigating the in vitro activities of amoxicillin-clavulanate, doxycycline, ceftazidime, imipenem, and trimethoprim-sulfamethoxazole against Burkholderia pseudomallei in planktonic and biofilm forms, through broth microdilution and resazurin-based viability staining, respectively. In planktonic growth, the strains were susceptible to the drugs, while in biofilm growth, significantly higher antimicrobial concentrations were required, especially for ceftazidime and imipenem, surpassing the resistance breakpoints. These results highlight the importance of the routine evaluation of biofilm antimicrobial susceptibility.

Doxycycline-encapsulated nanotube-modified dentin adhesives.

PubMed

Feitosa, S A; Palasuk, J; Kamocki, K; Geraldeli, S; Gregory, R L; Platt, J A; Windsor, L J; Bottino, M C

2014-12-01

This article presents details of fabrication, biological activity (i.e., anti-matrix metalloproteinase [anti-MMP] inhibition), cytocompatibility, and bonding characteristics to dentin of a unique doxycycline (DOX)-encapsulated halloysite nanotube (HNT)-modified adhesive. We tested the hypothesis that the release of DOX from the DOX-encapsulated nanotube-modified adhesive can effectively inhibit MMP activity. We incorporated nanotubes, encapsulated or not with DOX, into the adhesive resin of a commercially available bonding system (Scotchbond Multi-Purpose [SBMP]). The following groups were tested: unmodified SBMP (control), SBMP with nanotubes (HNT), and DOX-encapsulated nanotube-modified adhesive (HNT+DOX). Changes in degree of conversion (DC) and microtensile bond strength were evaluated. Cytotoxicity was examined on human dental pulp stem cells (hDPSCs). To prove the successful encapsulation of DOX within the adhesives-but, more important, to support the hypothesis that the HNT+DOX adhesive would release DOX at subantimicrobial levels-we tested the antimicrobial activity of synthesized adhesives and the DOX-containing eluates against Streptococcus mutans through agar diffusion assays. Anti-MMP properties were assessed via β-casein cleavage assays. Increasing curing times (10, 20, 40 sec) led to increased DC values. There were no statistically significant differences (p > .05) in DC within each increasing curing time between the modified adhesives compared to SBMP. No statistically significant differences in microtensile bond strength were noted. None of the adhesives eluates were cytotoxic to the human dental pulp stem cells. A significant growth inhibition of S. mutans by direct contact illustrates successful encapsulation of DOX into the experimental adhesive. More important, DOX-containing eluates promoted inhibition of MMP-1 activity when compared to the control. Collectively, our findings provide a solid background for further testing of encapsulated MMP

Doxycycline-Encapsulated Nanotube-Modified Dentin Adhesives

PubMed Central

Feitosa, S.A.; Palasuk, J.; Kamocki, K.; Geraldeli, S.; Gregory, R.L.; Platt, J.A.; Windsor, L.J.; Bottino, M.C.

2014-01-01

This article presents details of fabrication, biological activity (i.e., anti–matrix metalloproteinase [anti-MMP] inhibition), cytocompatibility, and bonding characteristics to dentin of a unique doxycycline (DOX)–encapsulated halloysite nanotube (HNT)–modified adhesive. We tested the hypothesis that the release of DOX from the DOX-encapsulated nanotube-modified adhesive can effectively inhibit MMP activity. We incorporated nanotubes, encapsulated or not with DOX, into the adhesive resin of a commercially available bonding system (Scotchbond Multi-Purpose [SBMP]). The following groups were tested: unmodified SBMP (control), SBMP with nanotubes (HNT), and DOX-encapsulated nanotube-modified adhesive (HNT+DOX). Changes in degree of conversion (DC) and microtensile bond strength were evaluated. Cytotoxicity was examined on human dental pulp stem cells (hDPSCs). To prove the successful encapsulation of DOX within the adhesives—but, more important, to support the hypothesis that the HNT+DOX adhesive would release DOX at subantimicrobial levels—we tested the antimicrobial activity of synthesized adhesives and the DOX-containing eluates against Streptococcus mutans through agar diffusion assays. Anti-MMP properties were assessed via β-casein cleavage assays. Increasing curing times (10, 20, 40 sec) led to increased DC values. There were no statistically significant differences (p > .05) in DC within each increasing curing time between the modified adhesives compared to SBMP. No statistically significant differences in microtensile bond strength were noted. None of the adhesives eluates were cytotoxic to the human dental pulp stem cells. A significant growth inhibition of S. mutans by direct contact illustrates successful encapsulation of DOX into the experimental adhesive. More important, DOX-containing eluates promoted inhibition of MMP-1 activity when compared to the control. Collectively, our findings provide a solid background for further testing of

Doxycycline as an inhibitor of p-glycoprotein in the alpaca for the purpose of maintaining avermectins in the CNS during treatment for parelaphostrongylosis.

PubMed

Agbedanu, Prince N; Anderson, Kristi L; Brewer, Matthew T; Carlson, Steve A

2015-09-15

Meningeal worms (Parelaphostrongylus tenuis) are a common malady of alpacas, often refractory to conventional treatments. Ivermectin is a very effective anthelmintic used against a variety of parasites but this drug is not consistently effective against alpaca meningeal worms once the parasite has gained access to the CNS, even if used in a protracted treatment protocol. Ivermectin is not effective against clinical cases of P. tenuis, raising the possibility that the drug is not sustained at therapeutic concentrations in the central nervous system (CNS). A specific protein (designated as p-glycoprotein (PGP)) effluxes ivermectin from the brain at the blood-brain barrier, thus hampering the maintenance of therapeutic concentrations of the drug in the CNS. Minocycline is a synthetic tetracycline antibiotic with an excellent safety profile in all animals tested to date. Minocycline has three unique characteristics that could be useful for treating meningeal worms in conjunction with ivermectin. First, minocycline is an inhibitor of PGP at the blood-brain barrier and this inhibition could maintain effective concentrations of ivermectin in the brain and meninges. Second, minocycline protects neurons in vivo through a number of different mechanisms and this neuroprotection could alleviate the potential untoward neurologic effects of meningeal worms. Third, minocycline is a highly lipid-soluble drug, thus facilitating efficient brain penetration. We thus hypothesized that minocycline will maintain ivermectin, or a related avermectin approved in ruminants (abamectin, doramectin, or eprinomectin), in the alpaca CNS. To test this hypothesis, we cloned the gene encoding the alpaca PGP, expressed the alpaca PGP in a heterologous expression system involving MDCK cells, and measured the ability of minocycline to inhibit the efflux of avermectins from the MDCK cells; doxycycline was used as a putative negative control (based on studies in other species). Our in vitro studies

Structural and functional alterations in rhodamine-123- and doxycycline-photosensitized cells

NASA Astrophysics Data System (ADS)

Shea, Christopher R.; Whitaker, Diana; Murphy, George F.; Chen, Norah; Wimberly, Joanne; Scholz, M.; Sherwood, M. E.; Flotte, Thomas J.; Hasan, Tayyaba

1990-06-01

In order to elucidate the mechanisms of photosensitized injury to mitochondria, two photosensitizers have been compared. Both doxycycline (DOTC) and rhodamine-l23 (R123) localize preferentially within the mitochondria of MGH-IJ1 bladder carcinoma cells j1 vitro, and both sensitize phototoxic injury that is selective for mitochondria. Mitochondria of cells pretreated with DOTC and irradiated with UVA (1 J/cm2, 320-400 rim) undergo massive swelling that begins by 10 mm after irradiation, is maximal by 1 h, and is partially repaired by 4 h; damage caused by exposure to a higher UVA dose (6 J/cm2), however, is not repaired. In contrast, cells pretreated with R123 and irradiated with an argon-ion laser (10 J/cm2, 514.5 rim) undergo a different type of mitochondrial injury, characterized by the delayed (4 h) onset of moderate mitochondrial swelling and striking mitochondrial distortion and fragmentation, which is not repaired by 48 h after irradiation. These differences indicate that the reactions underlying cellular phototoxicity can be distinguished even on an ultrastructural level. Probably both the primary photochemistry and the submitochondrial targets of these reactions differ with the two photosensitizers.

Highly sensitive spectrofluorimetric determination of trace amounts NADP using Europium ion-doxycycline complex probe

NASA Astrophysics Data System (ADS)

Peng, Qian; Hou, Faju; Jiang, Chongqiu

2006-09-01

A new spectrofluorimetric method was developed for determination of trace amount of Coenzyme II (NADP). Using europium ion-doxycycline (DC) as a fluorescent probe, in the buffer solution of pH 8.44, NADP can remarkably enhance the fluorescence intensity of the Eu 3+-DC complex at λ = 612 nm and the enhanced fluorescence intensity is in proportion to the concentration of NADP. Optimum conditions for the determination of NADP were also investigated. The dynamic range for the determination of NADP is 3.3 × 10 -7 to 6.1 × 10 -6 mol l -1 with detection limit of 6.8 × 10 -8 mol l -1. This method is simple, practical and relatively free interference from coexisting substances and can be successfully applied to determination of NADP in synthetic water samples and in serum samples. Moreover, the enhancement mechanisms of the fluorescence intensity in the Eu 3+-DC system and the Eu 3+-DC-NADP system have been also discussed.

Effective Delivery of Doxycycline and Epidermal Growth Factor for Expedited Healing of Chronic Wounds

NASA Astrophysics Data System (ADS)

Kulkarni, Abhilash

The problems and high medical costs associated with chronic wounds necessitate an economical bioactive wound dressing. A new strategy was investigated to inhibit MMP-9 proteases and to release epidermal growth factor (EGF) to enhance healing. Doxycycline (DOX) and EGF were encapsulated on polyacrylic acid modified polyurethane film (PAA-PU) using Layer-by-Layer (LbL) assembly. The number of bilayers tuned the concentration of DOX and EGF released over time with over 94% bioactivity of EGF retained over 4 days. A simple wound model in which MMP-9 proteases were added to cell culture containing fibroblast cells demonstrated that DOX inhibited the proteases providing a protective environment for the released EGF to stimulate cell migration and proliferation at a faster healing rate. In the presence of DOX, only small amounts of the highly bioactive EGF are sufficient to close the wound. Results show that this is new and promising bioactive dressing for effective wound management.

Lyme neuroborreliosis in HIV-1 positive men successfully treated with oral doxycycline: a case series and literature review

PubMed Central

2011-01-01

Introduction Lyme neuroborreliosis is the most common bacterial central nervous system infection in the temperate parts of the northern hemisphere. Even though human immunodeficiency virus (HIV) -1 infection is common in Lyme borreliosis endemic areas, only five cases of co-infection have previously been published. Four of these cases presented with typical Lyme neuroborreliosis symptoms such as meningoradiculitis and facial palsy, while a fifth case had more severe symptoms of encephalomyelitis. All five were treated with intravenous cephalosporins and clinical outcome was good for all but the fifth case Case presentations We present four patients with concomitant presence of HIV-1 infection and Lyme neuroborreliosis diagnosed in Western Sweden. Patient 1 was a 60-year-old Caucasian man with radicular pain and cognitive impairment. Patient 2 was a 39-year-old Caucasian man with headaches, leg weakness, and pontine infarction. Patient 3 was a 62-year-old Caucasian man with headaches, tremor, vertigo, and normal-pressure hydrocephalus. Patient 4 was a 50-year-old Caucasian man with radicular pain and peripheral facial palsy. Patients one, two, and three all had subnormal levels of CD4 cells, indicating impaired immunity. All patients were treated with oral doxycycline with good clinical outcome and normalization of CSF pleocytosis. Conclusion Given the low HIV-1 prevalence and medium incidence of Lyme neuroborreliosis in Western Sweden where these four cases were diagnosed, co-infection with HIV-1 and Borrelia is probably more common than previously thought. The three patients that were the most immunocompromised suffered from more severe and rather atypical neurological symptoms than are usually described among patients with Lyme neuroborreliosis. It is therefore important for doctors treating HIV patients to consider Lyme neuroborreliosis in a patient presenting with atypical neurological symptoms. All four patients were treated with oral doxycycline with a good

Lyme neuroborreliosis in HIV-1 positive men successfully treated with oral doxycycline: a case series and literature review.

PubMed

Bremell, Daniel; Säll, Christer; Gisslén, Magnus; Hagberg, Lars

2011-09-19

Lyme neuroborreliosis is the most common bacterial central nervous system infection in the temperate parts of the northern hemisphere. Even though human immunodeficiency virus (HIV) -1 infection is common in Lyme borreliosis endemic areas, only five cases of co-infection have previously been published. Four of these cases presented with typical Lyme neuroborreliosis symptoms such as meningoradiculitis and facial palsy, while a fifth case had more severe symptoms of encephalomyelitis. All five were treated with intravenous cephalosporins and clinical outcome was good for all but the fifth case We present four patients with concomitant presence of HIV-1 infection and Lyme neuroborreliosis diagnosed in Western Sweden. Patient 1 was a 60-year-old Caucasian man with radicular pain and cognitive impairment. Patient 2 was a 39-year-old Caucasian man with headaches, leg weakness, and pontine infarction. Patient 3 was a 62-year-old Caucasian man with headaches, tremor, vertigo, and normal-pressure hydrocephalus. Patient 4 was a 50-year-old Caucasian man with radicular pain and peripheral facial palsy. Patients one, two, and three all had subnormal levels of CD4 cells, indicating impaired immunity. All patients were treated with oral doxycycline with good clinical outcome and normalization of CSF pleocytosis. Given the low HIV-1 prevalence and medium incidence of Lyme neuroborreliosis in Western Sweden where these four cases were diagnosed, co-infection with HIV-1 and Borrelia is probably more common than previously thought. The three patients that were the most immunocompromised suffered from more severe and rather atypical neurological symptoms than are usually described among patients with Lyme neuroborreliosis. It is therefore important for doctors treating HIV patients to consider Lyme neuroborreliosis in a patient presenting with atypical neurological symptoms. All four patients were treated with oral doxycycline with a good outcome, further proving the efficacy of

Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure

PubMed Central

Riba, Adam; Deres, Laszlo; Eros, Krisztian; Szabo, Aliz; Magyar, Klara; Sumegi, Balazs; Toth, Kalman; Halmosi, Robert; Szabados, Eszter

2017-01-01

In addition to their anti-bacterial action, tetracyclines also have complex biological effects, including the modification of mitochondrial protein synthesis, metabolism and gene-expression. Long-term clinical studies have been performed using tetracyclines, without significant side effects. Previous studies demonstrated that doxycycline (DOX), a major tetracyclin antibiotic, exerted a protective effect in animal models of heart failure; however, its exact molecular mechanism is still unknown. Here, we provide the first evidence that DOX reduces oxidative stress—induced mitochondrial fragmentation and depolarization in H9c2 cardiomyocytes and beneficially alters the expression of Mfn-2, OPA-1 and Drp-1 –the main regulators of mitochondrial fusion and fission—in our isoproterenol (ISO)–induced heart failure model, ultimately decreasing the severity of heart failure. In mitochondria, oxidative stress causes a shift toward fission which leads to mitochondrial fragmentation and cell death. Protecting mitochondria from oxidative stress, and the regulation of mitochondrial dynamics by drugs that shift the balance toward fusion, could be a novel therapeutic approach for heart failure. On the basis of our findings, we raise the possibility that DOX could be a novel therapeutic agent in the future treatment of heart failure. PMID:28384228

A randomized-controlled trial of low-dose doxycycline for periodontitis in smokers

PubMed Central

Needleman, Ian; Suvan, Jean; Gilthorpe, Mark S.; Tucker, Richard; St George, Geoff; Giannobile, William; Tonetti, Maurizio; Jarvis, Martin

2008-01-01

Background/Aim Tobacco use reduces the effect of non-surgical periodontal therapy. Host-modulation with low-dose doxycycline (LDD) might favour repair and promote an improved treatment response. The aim of this study was to investigate the effect of LDD in smokers on non-surgical periodontal therapy. Material and Methods This was a parallel arm, randomized, identical placebo-controlled trial with masking of examiner, care-giver, participant and statistician and 6 months of follow-up. Patients received non-surgical therapy and 3 months of test or control drug. Statistical analysis used both conventional methods and multilevel modelling. Results Eighteen control and 16 test patients completed the study. The velocity of change was statistically greater for the test group for clinical attachment level −0.19 mm/month (95% CI= −0.34, 0.04; p=0.012) and probing depth 0.30 mm/month (95% CI= −0.42, −0.17; p < 0.001). However, no differences were observed for absolute change in clinical or biochemical markers at 6 months. Conclusions This study does not provide evidence of a benefit of using LDD as an adjunct to non-surgical periodontal therapy in smokers. PMID:17324155

Advanced oxidation processes on doxycycline degradation: monitoring of antimicrobial activity and toxicity.

PubMed

Spina-Cruz, Mylena; Maniero, Milena Guedes; Guimarães, José Roberto

2018-05-08

Advanced oxidation processes (AOPs) have been highly efficient in degrading contaminants of emerging concern (CEC). This study investigated the efficiency of photolysis, peroxidation, photoperoxidation, and ozonation at different pH values to degrade doxycycline (DC) in three aqueous matrices: fountain, tap, and ultrapure water. More than 99.6% of DC degradation resulted from the UV/H 2 O 2 and ozonation processes. Also, to evaluate the toxicity of the original solution and throughout the degradation time, antimicrobial activity tests were conducted using Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli) bacteria, and acute toxicity test using the bioluminescent marine bacterium (Vibrio fischeri). Antimicrobial activity reduced as the drug degradation increased in UV/H 2 O 2 and ozonation processes, wherein the first process only 6 min was required to reduce 100% of both bacteria activity. In ozonation, 27.7 mg L -1 of ozone was responsible for reducing 100% of the antimicrobial activity. When applied the photoperoxidation process, an increase in the toxicity occurred as the high levels of degradation were achieved; it means that toxic intermediates were formed. The ozonated solutions did not present toxicity.

AIO LQ-0110: a randomized phase II trial comparing oral doxycycline versus local administration of erythromycin as preemptive treatment strategies of panitumumab-mediated skin toxicity in patients with metastatic colorectal cancer.

PubMed

Kripp, Melanie; Prasnikar, Nicole; Vehling-Kaiser, Ursula; Quidde, Julia; Al-Batran, Salah-Eddin; Stein, Alexander; Neben, Kai; Hannig, Carla Verena; Tessen, Hans Werner; Trarbach, Tanja; Hinke, Axel; Hofheinz, Ralf-Dieter

2017-12-01

Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm ( P = n.s .). However, as per WoMo score significantly more patients in the erythromycin arm developed moderate or severe skin toxicity at earlier time points. Skin related and overall quality of life was comparable between both arms. Based on this data erythromycin cannot be regarded as an alternative to doxycycline as prevention of EGFR-related skin toxicity.

Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice.

PubMed

Merentie, Mari; Rissanen, Riina; Lottonen-Raikaslehto, Line; Huusko, Jenni; Gurzeler, Erika; Turunen, Mikko P; Holappa, Lari; Mäkinen, Petri; Ylä-Herttuala, Seppo

2018-01-01

Vascular endothelial growth factor-A (VEGF-A) is the master regulator of angiogenesis, vascular permeability and growth. However, its role in mature blood vessels is still not well understood. To better understand the role of VEGF-A in the adult vasculature, we generated a VEGF-A knockdown mouse model carrying a doxycycline (dox)-regulatable short hairpin RNA (shRNA) transgene, which silences VEGF-A. The aim was to find the critical level of VEGF-A reduction for vascular well-being in vivo. In vitro, the dox-inducible lentiviral shRNA vector decreased VEGF-A expression efficiently and dose-dependently in mouse endothelial cells and cardiomyocytes. In the generated transgenic mice plasma VEGF-A levels decreased shortly after the dox treatment but returned back to normal after two weeks. VEGF-A expression decreased shortly after the dox treatment only in some tissues. Surprisingly, increasing the dox exposure time and dose led to elevated VEGF-A expression in some tissues of both wildtype and knockdown mice, suggesting that dox itself has an effect on VEGF-A expression. When the effect of dox on VEGF-A levels was further tested in naïve/non-transduced cells, the dox administration led to a decreased VEGF-A expression in endothelial cells but to an increased expression in cardiomyocytes. In conclusion, the VEGF-A knockdown was achieved in a dox-regulatable fashion with a VEGF-A shRNA vector in vitro, but not in the knockdown mouse model in vivo. Dox itself was found to regulate VEGF-A expression explaining the unexpected results in mice. The effect of dox on VEGF-A levels might at least partly explain its previously reported beneficial effects on myocardial and brain ischemia. Also, this effect on VEGF-A should be taken into account in all studies using dox-regulated vectors.

Validated spectrophotometric methods for simultaneous determination of Omeprazole, Tinidazole and Doxycycline in their ternary mixture

NASA Astrophysics Data System (ADS)

Lotfy, Hayam M.; Hegazy, Maha A.; Mowaka, Shereen; Mohamed, Ekram Hany

2016-01-01

A comparative study of smart spectrophotometric techniques for the simultaneous determination of Omeprazole (OMP), Tinidazole (TIN) and Doxycycline (DOX) without prior separation steps is developed. These techniques consist of several consecutive steps utilizing zero/or ratio/or derivative spectra. The proposed techniques adopt nine simple different methods, namely direct spectrophotometry, dual wavelength, first derivative-zero crossing, amplitude factor, spectrum subtraction, ratio subtraction, derivative ratio-zero crossing, constant center, and successive derivative ratio method. The calibration graphs are linear over the concentration range of 1-20 μg/mL, 5-40 μg/mL and 2-30 μg/mL for OMP, TIN and DOX, respectively. These methods are tested by analyzing synthetic mixtures of the above drugs and successfully applied to commercial pharmaceutical preparation. The methods that are validated according to the ICH guidelines, accuracy, precision, and repeatability, were found to be within the acceptable limits.

Treatment efficacy of azithromycin 1 g single dose versus doxycycline 100 mg twice daily for 7 days for the treatment of rectal chlamydia among men who have sex with men - a double-blind randomised controlled trial protocol.

PubMed

Lau, Andrew; Kong, Fabian; Fairley, Christopher K; Donovan, Basil; Chen, Marcus; Bradshaw, Catriona; Boyd, Mark; Amin, Janaki; Timms, Peter; Tabrizi, Sepehr; Regan, David G; Lewis, David A; McNulty, Anna; Hocking, Jane S

2017-01-06

Rectal infection with Chlamydia trachomatis is one of the most common bacterial sexually transmissible infections among men who have sex with men (MSM) with diagnosis rates continuing to rise. Current treatment guidelines recommend either azithromycin 1 g single dose or doxycycline 100 mg twice daily for 7 days. However, there are increasing concerns about treatment failure with azithromycin. We are conducting the first randomised controlled trial (RCT) to compare treatment efficacy of azithromycin versus doxycycline for the treatment of rectal chlamydia in MSM. The Rectal Treatment Study will recruit 700 MSM attending Australian sexual health clinics for the treatment of rectal chlamydia. Participants will be asked to provide rectal swabs and will be randomised to either azithromycin 1 g single dose or doxycycline 100 mg twice daily for 7 days. Participants will be asked to complete questionnaires about adverse drug reactions, sexual behaviour and drug adherence via short message service and online survey. The primary outcome is the treatment efficacy as determined by a negative chlamydia nucleic acid amplification test at 4 weeks post treatment. Secondary outcomes will utilise whole genome sequencing and mRNA assay to differentiate between treatment failure, reinfection or false positive results. Rectal chlamydia is an increasing public health concern as use of pre-exposure prophylaxis against HIV becomes commonplace. Optimal, evidence-based treatment is critical to halting ongoing transmission. This study will provide the first RCT evidence comparing azithromycin and doxycycline for the treatment of rectal chlamydia. The results of this trial will establish which treatment is more efficacious and inform international management guidelines. Australian New Zealand Clinical Trials Registry ACTRN12614001125617.

A randomized controlled trial to compare the safety and effectiveness of doxycycline (200 mg daily) with oral prednisolone (0.5 mg kg(-1) daily) for initial treatment of bullous pemphigoid: a protocol for the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) Trial.

PubMed

Chalmers, J R; Wojnarowska, F; Kirtschig, G; Nunn, A J; Bratton, D J; Mason, J; Foster, K A; Whitham, D; Williams, H C

2015-07-01

Bullous pemphigoid (BP) is the most common autoimmune blistering disease in older people, and is associated with significant morbidity and mortality. Oral corticosteroids are usually effective but the side-effects are thought to contribute to the high morbidity and mortality rate. Treatment with oral tetracyclines may be effective but high-quality, randomized controlled trials (RCTs) are needed to confirm this. To compare the effectiveness and safety of two strategies for treating BP. This is a two-arm, parallel group, 52-week RCT comparing doxycycline with prednisolone for initial treatment of BP. Dose is fixed for the initial 6 weeks of treatment (doxycycline 200 mg daily; prednisolone 0.5 mg kg(-1) daily), after which it can be adjusted according to need. A total of 256 patients with BP will be recruited in the U.K. and Germany. The primary outcomes are: (i) effectiveness (assessor-blinded blister count at 6 weeks) and (ii) safety [proportion of patients experiencing ≥ grade 3 adverse events (i.e. severe, life: threatening or fatal) related to trial medication during the year of follow-up]. Primary effectiveness analysis will be an assessment of whether doxycycline can be considered noninferior to prednisolone after 6 weeks of treatment. Primary safety analysis is a superiority analysis at 12 months. Secondary outcomes include longer-term assessment of effectiveness, relapse rates, the proportion of patients experiencing any grade of adverse events related to treatment, quality of life and cost-effectiveness. The trial will provide good evidence for whether the strategy of starting BP treatment with doxycycline is a useful alternative to prednisolone. © 2015 British Association of Dermatologists.

Comprehensive Adsorption Studies of Doxycycline and Ciprofloxacin Antibiotics by Biochars Prepared at Different Temperatures

PubMed Central

Zeng, Zhi-wei; Tan, Xiao-fei; Liu, Yun-guo; Tian, Si-rong; Zeng, Guang-ming; Jiang, Lu-hua; Liu, Shao-bo; Li, Jiang; Liu, Ni; Yin, Zhi-hong

2018-01-01

This paper comparatively investigated the removal efficiency and mechanisms of rice straw biochars prepared under three pyrolytic temperatures for two kinds of tetracycline and quinolone antibiotics (doxycycline and ciprofloxacin). The influencing factors of antibiotic adsorption (including biochar dosage, pH, background electrolytes, humic acid, initial antibiotics concentration, contact time, and temperature) were comprehensively studied. The results suggest that biochars produced at high-temperature [i.e., 700°C (BC700)], have higher adsorption capacity for the two antibiotics than low-temperature (i.e., 300–500°C) biochars (BC300 and BC500). Higher surface area gives rise to greater volume of micropores and mesopores, and higher graphitic surfaces of the BC700 contributed to its higher functionality. The maximum adsorption capacity was found to be in the following order: DOX > CIP. The π-π EDA interaction and hydrogen bonding might be the predominant adsorption mechanisms. Findings in this study highlight the important roles of high-temperature biochars in controlling the contamination of tetracycline and quinolone antibiotics in the environment. PMID:29637067

Comprehensive adsorption studies of doxycycline and ciprofloxacin antibiotics by biochars prepared at different temperatures

NASA Astrophysics Data System (ADS)

Zeng, Zhi-wei; Tan, Xiao-fei; Liu, Yun-guo; Tian, Si-rong; Zeng, Guang-ming; Jiang, Lu-hua; Liu, Shao-bo; Li, Jiang; Liu, Ni; Yin, Zhi-hong

2018-03-01

This paper comparatively investigated the removal efficiency and mechanisms of rice straw biochars prepared under three pyrolytic temperatures for two kinds of tetracycline and quinolone antibiotics (doxycycline and ciprofloxacin). The influencing factors of antibiotic adsorption (including biochar dosage, pH, background electrolytes, humic acid, initial antibiotics concentration, contact time, and temperature) were comprehensively studied. The results suggest that biochars produced at high-temperature (i.e., 700°C (BC700)), have higher adsorption capacity for the two antibiotics than low-temperature (i.e., 300-500°C) biochars (BC300 and BC500). Higher surface area gives rise to greater volume of micropores and mesopores, and higher graphitic surfaces of the BC700 contributed to its higher functionality. The maximum adsorption capacity was found to be in the following order: DOX > CIP. The π-π EDA interaction and hydrogen bonding might be the predominant adsorption mechanisms. Findings in this study highlight the important roles of high-temperature biochars in controlling the contamination of tetracycline and quinolone antibiotics in the environment.

Regenerative surgical therapy for peri-implantitis using deproteinized bovine bone mineral with 10% collagen, enamel matrix derivative and Doxycycline-A prospective 3-year cohort study.

PubMed

Mercado, Faustino; Hamlet, Stephen; Ivanovski, Saso

2018-05-16

There is limited evidence regarding the long-term efficacy of regenerative treatment for peri-implantitis. The aim of this study was to evaluate a combination therapy of deproteinized bovine bone mineral with 10% collagen (DBBMC), enamel matrix derivative (EMD) and Doxycycline in the regeneration of bone defects associated with peri-implantitis. Thirty patients diagnosed with peri-implantitis (BoP/suppuration, probing depth greater than 4 mm, minimum radiographic bone loss of 20%, at least 2 years in function) were enrolled in the study. Clinical measurements included probing depths, recession, radiographic bone fill, gingival inflammation and bleeding on probing/suppuration. Following surgical access and debridement, the implant surfaces were decontaminated with 24% EDTA for 2 min, and the bone defects were filled with a combined mixture of DBBMC, EMD and Doxycycline powder. The defects were covered with connective tissue grafts where necessary. Clinical measurements were recorded after 12, 24 and 36 months. The mean probing depth and bone loss at the initial visit was 8.9 mm (±1.9) and 6.92 mm (±1.26), respectively. Both mean probing depth and bone loss reduced significantly from baseline to 3.55 mm (±0.50) and 2.85 mm (±0.73) at 12 months, 3.50 (±0.50) and 2.62 mm (±0.80) at 24 months and 3.50 mm (±0.50) and 2.60 mm (±0.73) at 36 months. 56.6% of the implants were considered successfully treated (according to Successful Treatment Outcome Criterion: PD < 5 mm, no further bone loss >10%, no BoP/suppuration, no recession >0.5 mm for anterior implants and >1.5 mm for posterior implants) after 36 months. Regenerative treatment of peri-implantitis using a combined mixture of DBBMC, EMD and Doxycycline achieved promising results. The benefits of this protocol incorporating EMD should be tested in randomized clinical trials. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Doxycycline induces bone repair and changes in Wnt signalling

PubMed Central

Gomes, Kátia do Nascimento; Alves, Ana Paula Negreiros Nunes; Dutra, Paula Góes Pinheiro; Viana, Glauce Socorro de Barros

2017-01-01

Doxycycline (DOX) exhibits anti-inflammatory and MMP inhibitory properties. The objectives of this study were to evaluate the effects of DOX on alveolar bone repair. Controls (CTL) and DOX-treated (10 and 25 mg·kg−1) molars were extracted, and rats were killed 7 or 14 days later. The maxillae were processed and subjected to histological and immunohistochemical assays. Hematoxylin-eosin staining (7th day) revealed inflammation in the CTL group that was partly reversed after DOX treatment. On the 14th day, the CTL group exhibited bone neoformation, conjunctive tissue, re-epithelization and the absence of inflammatory infiltrate. DOX-treated groups exhibited complete re-epithelization, tissue remodelling and almost no inflammation. Picrosirius red staining in the DOX10 group (7th and 14th days) revealed an increased percentage of type I and III collagen fibres compared with the CTL and DOX25 groups. The DOX10 and DOX25 groups exhibited increases in osteoblasts on the 7th and 14th days. However, there were fewer osteoclasts in the DOX10 and DOX25 groups on the 7th and 14th days. Wnt-10b-immunopositive cells increased by 130% and 150% on the 7th and 14th days, respectively, in DOX-treated groups compared with the CTL group. On the 7th day, Dickkopf (Dkk)-1 immunostaining was decreased by 63% and 46% in the DOX10 and DOX25 groups, respectively. On the 14th day, 69% and 42% decreases in immunopositive cells were observed in the DOX10 and DOX25 groups, respectively, compared with the CTL group. By increasing osteoblasts, decreasing osteoclasts, activating Wnt 10b and neutralising Dkk, DOX is a potential candidate for bone repair in periodontal diseases. PMID:28960195

Antioxidant Response of Osteoblasts to Doxycycline in an Inflammatory Model Induced by C-reactive Protein and Interleukin-6

PubMed Central

Tilakaratne, A.; Soory, Mena

2016-01-01

Objectives: Investigation of osteoblastic responses to oxidative stress, induced by C-reactive protein (CRP) and IL-6 and ameliorating effects of doxycycline (Dox); using assays for 5-alpha dihydrotestosterone (DHT) as an antioxidant marker of healing. IL-6 and CRP are risk markers of periodontitis and prevalent comorbidities in periodontitis subjects. Methods: Confluent monolayer cultures of osteoblasts were incubated with radiolabelled testosterone (14C-T) as substrate, in the presence or absence (Control) of pre-determined optimal concentrations of CRP, IL-6, Dox; alone and in combination (n=8) for 24h in MEM. The eluent was solvent-extracted for steroid metabolites. They were separated using TLC in a benzene/ acetone solvent system 4:1 v/v; and quantified using radioisotope scanning. The identity of formed metabolites was confirmed using the mobility of cold standards added to the samples and disclosed in iodine. Further confirmation of the authenticity of DHT was carried out by combined gas chromatrography-mass spectrometry, after derivatization to pentafluorobenzyloxime trimethyl silyl ether. Results: The yields of DHT from 14C-testosterone showed 2-fold and 1.8-fold- inhibition in response to IL-6 and CRP respectively and 28% stimulation in response to Dox, via the 5-alpha reductase pathway. The combination of IL-6 + CRP showed a 2-fold reduction in the yields of DHT, elevated to control values when combined with Dox (n=8; p<0.001). Yields of 4-androstenedione showed an inverse relationship to those of DHT, in response to the agents tested, in keeping with the 17-beta hydroxysteroid dehydrogenase pathway. Conclusions: Inhibition of DHT synthesis in osteoblasts by IL-6 and CRP was overcome by doxycycline. Oxidative actions of IL-6 and CRP; and antioxidant actions of Dox are reinforced by the metabolic yields of DHT in response to agents tested. Using a novel metabolically active model allows closer extrapolation to in vivo conditions; in the context of

The Effect of Systemic Delivery of Aminoguanidine versus Doxycycline on the Resorptive Phase of Alveolar Bone Following modified Widman Flap in Diabetic Rats: A Histopathological and Scanning Electron Microscope (SEM) study.

PubMed

Tella, E; Aldahlawi, S; Eldeeb, A; El Gazaerly, H

2014-07-01

Aminoguanidine (guanylhydrazinehydrochloride) is a drug that prevents many of the classical systemic complications of diabetes including diabetic osteopenia through its inhibitory activity on the accumulation of advanced glycation end -products (AGEs). The aim of the present study was to evaluate the effectiveness of aminoguanidine versus doxycycline in reducing alveolar bone resorption following mucoperiosteal flap in diabetic rats, using the conventional histopathology and scanning electron microscope (SEM). Twenty-seven male albino rats were used in this study. Periodontal defects were induced experimentally on lower anterior teeth. All rats were subjected to induction of diabetes, by IV injection of the pancreatic B-cells toxin alloxan monohydrate. After eight weeks following the establishment of periodontal defects in all rats, the ligation was removed and 3 rats were scarified as negative control (group 1). The remaining animals were divided into three group based on treatment applied following mucoperiosteal flap surgery. Group 2 received saline treatment only, group 3 received doxycycline periostat (1.5 mg/kg/day) for 3 weeks, and group 4 received aminoguanidine (7.3 mmol/kg) for 3 weeks. The fasting glucose level was measured weekly post operatively. After 21 days all rats were sacrificed. Three anterior parts of the mandible of each group was prepared for histopathological examination and two parts were prepared for SEM. Aminoguanidine treated group (group 4) showed statistically significant increased new bone formation, higher number of osteoblasts and decrease osteoclasts number, resorptive lacunae and existing inflammatory cell infiltration as compared to positive control group (group 2) (P<0.05). Doxycycline was also effective in reducing bone loss as documental by histopathological study. The present study showed that aminoguanidine was significantly effective in reducing alveolar bone loss and can modify the detrimental effects of diabetes in

Cloning and characterization of an adenoviral vector for highly efficient and doxycycline – suppressible expression of bioactive human single – chain interleukin 12 in colon cancer

PubMed Central

Wulff, Holger; Krieger, Thorsten; Krüger, Karen; Stahmer, Ingrid; Thaiss, Friedrich; Schäfer, Hansjörg; Block, Andreas

2007-01-01

Background Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12. Results High gene expression was obtained utilizing the VP16 herpes simplex transactivator. Strong regulation of gene expression was realized by fusion of the VP16 to a tetracycline repressor with binding of the fusion protein to a flanking tetracycline operator and further enhanced by auto-regulated expression of its fusion gene within a bicistronic promoter construct. Infection of human colon cancer cells (HT29) at a multiplicity of infection (m.o.i.) of 10 resulted in the production of up to 8000 ng/106 cells in 48 h, thus exceeding any published vector system so far. Doxycycline concentrations as low as 30 ng/ml resulted in up to 5000-fold suppression, enabling significant reduction of gene expression in a possible clinical setting. Bioactivity of the human single-chain IL-12 was similar to purified human heterodimeric IL-12. Frozen sections of human colon cancer showed high expression of the coxsackie adenovirus receptor with significant production of human single chain IL-12 in colon cancer biopsies after infection with 3*107 p.f.u. Ad.3r-scIL12. Doxycycline mediated suppression of gene expression was up to 9000-fold in the infected colon cancer tissue. Conclusion VP16 transactivator-mediated and

HPLC and chemometrics-assisted UV-spectroscopy methods for the simultaneous determination of ambroxol and doxycycline in capsule.

PubMed

Hadad, Ghada M; El-Gindy, Alaa; Mahmoud, Waleed M M

2008-08-01

High-performance liquid chromatography (HPLC) and multivariate spectrophotometric methods are described for the simultaneous determination of ambroxol hydrochloride (AM) and doxycycline (DX) in combined pharmaceutical capsules. The chromatographic separation was achieved on reversed-phase C(18) analytical column with a mobile phase consisting of a mixture of 20mM potassium dihydrogen phosphate, pH 6-acetonitrile in ratio of (1:1, v/v) and UV detection at 245 nm. Also, the resolution has been accomplished by using numerical spectrophotometric methods as classical least squares (CLS), principal component regression (PCR) and partial least squares (PLS-1) applied to the UV spectra of the mixture and graphical spectrophotometric method as first derivative of the ratio spectra ((1)DD) method. Analytical figures of merit (FOM), such as sensitivity, selectivity, analytical sensitivity, limit of quantitation and limit of detection were determined for CLS, PLS-1 and PCR methods. The proposed methods were validated and successfully applied for the analysis of pharmaceutical formulation and laboratory-prepared mixtures containing the two component combination.

HPLC and chemometrics-assisted UV-spectroscopy methods for the simultaneous determination of ambroxol and doxycycline in capsule

NASA Astrophysics Data System (ADS)

Hadad, Ghada M.; El-Gindy, Alaa; Mahmoud, Waleed M. M.

2008-08-01

High-performance liquid chromatography (HPLC) and multivariate spectrophotometric methods are described for the simultaneous determination of ambroxol hydrochloride (AM) and doxycycline (DX) in combined pharmaceutical capsules. The chromatographic separation was achieved on reversed-phase C 18 analytical column with a mobile phase consisting of a mixture of 20 mM potassium dihydrogen phosphate, pH 6-acetonitrile in ratio of (1:1, v/v) and UV detection at 245 nm. Also, the resolution has been accomplished by using numerical spectrophotometric methods as classical least squares (CLS), principal component regression (PCR) and partial least squares (PLS-1) applied to the UV spectra of the mixture and graphical spectrophotometric method as first derivative of the ratio spectra ( 1DD) method. Analytical figures of merit (FOM), such as sensitivity, selectivity, analytical sensitivity, limit of quantitation and limit of detection were determined for CLS, PLS-1 and PCR methods. The proposed methods were validated and successfully applied for the analysis of pharmaceutical formulation and laboratory-prepared mixtures containing the two component combination.

Ciclosporin therapy for canine generalized discoid lupus erythematosus refractory to doxycycline and niacinamide.

PubMed

Banovic, Frane; Olivry, Thierry; Linder, Keith E

2014-10-01

Generalized discoid lupus erythematosus (DLE) is an autoimmune skin disease variant rarely reported in dogs. The antimalarial immunomodulator hydroxychloroquine has been suggested as maintenance therapy for generalized DLE in one dog, but several recurrences were noted in the 1 year follow-up of that patient. To describe the effective treatment of generalized DLE with ciclosporin in one dog. A 6-year-old, castrated male crossbred dog was presented with pruritic, well-demarcated annular to polycyclic, hyperpigmented plaques with marginal erythema on the dorsal head, neck, trunk and medial extremities; these had been nonresponsive to treatment with doxycycline and niacinamide. Investigation included complete blood count, serum chemistry profile, urinalysis, serum antinuclear antibody test, histopathological examination and direct immunofluorescence testing of skin biopsies. The presence of lymphocyte-rich interface dermatitis on histology, together with generalized chronic recurrent hyperpigmented plaques, was consistent with the diagnosis of a generalized variant of DLE. The absence of systemic signs and unremarkable laboratory tests excluded concurrent systemic lupus erythematosus. Treatment was initiated with oral dexamethasone and ciclosporin. After 1 month, dexamethasone was discontinued and oral ketoconazole was added to the therapeutic regimen. Four months later, pruritus and erythema resolved, with most skin lesions becoming impalpable. Over the last 6 months, the patient's DLE was maintained in remission with oral ciclosporin and ketoconazole in combination every 3 days. The combination of ciclosporin and ketoconazole appeared effective to induce and maintain lesion remission in this dog with generalized DLE. © 2014 ESVD and ACVD.

Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline.

PubMed

Yu, L P; Smith, G N; Brandt, K D; Myers, S L; O'Connor, B L; Brandt, D A

1992-10-01

In vitro studies have indicated that levels of neutral metalloproteinases in osteoarthritic (OA) cartilage are elevated and that doxycycline (doxy) inhibits collagenolytic and gelatinolytic activity in extracts of OA cartilage. The purpose of the present study was to test the effect of oral doxy administration on the severity of cartilage degeneration in OA. OA was induced in 12 adult mongrel dogs by transection of the anterior cruciate ligament (ACL) 2 weeks after dorsal root ganglionectomy. Six dogs received doxy orally from the day after ACL transection until they were killed 8 weeks later; the other 6 served as untreated OA controls. The unstable knee of each untreated dog exhibited extensive full-thickness cartilage ulceration of the medial femoral condyle. In sharp contrast, cartilage on the distal aspect of the femoral condyle of the unstable knee was grossly normal in 2 doxy-treated dogs, and exhibited only thinning and/or surface irregularity in the others. Degenerative cartilage lesions on the medial trochlear ridge, superficial fibrillation of the medial tibial plateau, and osteophytosis were, however, unaffected by doxy treatment. Collagenolytic activity and gelatinolytic activity in cartilage extracts from OA knees of untreated dogs were 5-fold and 4-fold greater, respectively, than in extracts from dogs given doxy. Prophylactic administration of doxy markedly reduced the severity of OA in weight-bearing regions of the medial femoral condyle. It remains to be determined whether administration of doxy after OA changes have developed is also effective.

[Study on the interaction of doxycycline with human serum albumin].

PubMed

Hu, Tao-Ying; Chen, Lin; Liu, Ying

2014-05-01

The present study was designed to investigate the interaction of doxycycline (DC) with human serum albumin (HSA) by the inner filter effects, displacement experiments and molecular docking methods, based on classic multi-spectroscopy. With fluorescence quenching method at 298 and 310 K, the binding constants Ka, were determined to be 2. 73 X 10(5) and 0. 74X 10(5) L mol-1, respectively, and there was one binding site between DC and HSA, indicating that the binding of DC to HSA was strong, and the quenching mechanism was a static quenching. The thermodynamic parameters (enthalpy change, AH and enthropy change, delta S) were calculated to be -83. 55 kJ mol-1 and -176. 31 J mol-1 K-1 via the Vant' Hoff equation, which indicated that the interaction of DC with HSA was driven mainly by hydrogen bonding and van der Waals forces. Based on the Föster's theory of non-radiation energy transfer, the specific binding distance between Trp-214 (acceptor) and DC (donor) was 4. 98 nm, which was similar to the result confirmed by molecular docking. Through displacement experiments, sub-domain IIA of HSA was assigned to possess the high-affinity binding site of DC. Three-dimensional fluorescence spectra indicated that the binding of DC to HSA induced the conformation change of HSA and increased the disclosure of some part of hydrophobic regions that had been buried before. The results of FTIR spectroscopy showed that DC bound to HSA led to the slight unfolding of the polypeptide chain of HSA. Furthermore, the binding details between DC and HSA were further confirmed by molecular docking methods, which revealed that DC was bound at sub-domain IIA through multiple interactions, such as hydrophobic effect, polar forces and pi-pi interactions. The experimental results provide theoretical basis and reliable data for the study of the interaction between small drug molecule and human serum albumin

Doxycycline hyclate-loaded bleached shellac in situ forming microparticle for intraperiodontal pocket local delivery.

PubMed

Phaechamud, Thawatchai; Chanyaboonsub, Nuttapong; Setthajindalert, Orn

2016-10-10

Bleached shellac (BS) is a water-insoluble polyester resin made up of sesquiterpenoid acids esterified with hydroxy aliphatic acids. In this study, BS dissolved in N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO) and 2-pyrrolidone was used as the internal phase of oil in oil emulsion using olive oil emulsified with glyceryl monostearate (GMS) as the external phase of in situ forming microparticles (ISM). Doxycycline hyclate (DH)-loaded BS ISMs were tested for emulsion stability, viscosity, rheology, transformation into microparticles, syringeability, drug release, surface topography, in vitro degradation and antimicrobial activities against Staphylococcus aureus, Streptococcus mutans and Porphyromonas gingivalis. All emulsions exhibited pseudoplastic flow and notably low syringeability force. Slower transformation from emulsion into microparticles of ISM prepared with 2-pyrrolidone was owing to slower solvent exchange of this solvent which promoted less porous structure of obtained BS matrix microparticles. The system containing 2-pyrrolidone exhibited a higher degradability than that prepared with DMSO. Developed DH-loaded BS ISMs exhibited a sustainable drug release for 47days with Fickian diffusion and effectively inhibited P. gingivalis, S. mutans and S. aureus. Therefore a DH-loaded BS ISM using olive oil containing GMS as the external phase and 2-pyrrolidone as a solvent was a suitable formulation for periodontitis treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Multicenter prospective study of treatment of Brucella melitensis brucellosis with doxycycline for 6 weeks plus streptomycin for 2 weeks.

PubMed Central

Cisneros, J M; Viciana, P; Colmenero, J; Pachón, J; Martinez, C; Alarcón, A

1990-01-01

The effectiveness of treating human brucellosis caused by Brucella melitensis with a 6-week course of doxcycline plus streptomycin for 2 of those weeks was analyzed by a multicenter prospective study of 139 patients. Subjects with central nervous system involvement, endocarditis, or spondylitis were excluded from the study. All but 5 of the 139 patients completed the full treatment schedule and became afebrile in the first week of therapy. Four patients suffered relapses during the follow-up period. Of the five patients who did not complete the treatment, two left because of adverse secondary effects (1.4%), another two left for noncomplicance with the treatment (1.4%), and the remaining patient was considered a therapeutic failure because his symptoms persisted after the first week of therapy (0.7%). We concluded that the combination of doxycycline and streptomycin is an effective treatment for the types of brucellosis included in our study. PMID:2193624

Doxycycline depletion and residues in eggs after oral administration to laying hens.

PubMed

Gajda, Anna; Posyniak, Andrzej

2015-01-01

The depletion of doxycycline (DC) residues in eggs was determined after oral drug administration by drinking water to laying hens. The antibiotic was supplied to birds for 5 consecutive days and the eggs were collected during medication and 18 days after withdrawal. DC residues were determined by LC-MS/MS. DC was isolated from eggs with a solution of 0.02 M of oxalic acid (pH 4), 0.1 M Na2EDTA and acetonitrile. The limit of detection (LOD) and limit of quantification (LOQ) of the method were 2 and 5 µg kg(-1), respectively. Analyses were performed on whole egg, egg white and yolk separately. DC was detectable 24 h after the beginning of administration. The concentration of antibiotic increased daily, resulting in the highest DC concentration in whole eggs at the first day of the withdrawal period. Thirteen days after withdrawal, the content of DC in whole eggs was below the LOQ of the method. However, some differences were found in the depletion curve of DC between egg white and yolk. Residues of DC in egg white were much higher during treatment and 1 day after withdrawal, but later the concentration in egg white decreased fairly rapidly and a higher DC content in egg yolk was observed. The depletion period was shorter for egg white than for yolk, and DC was detected in the egg white until 12 days after withdrawal and 2 days more in egg yolk than in white. DC reached a peak faster in egg white, but the residues were detectable for longer period in the yolk.

Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

PubMed Central

Batsa, Linda; Ayisi-Boateng, Nana Kwame; Osei-Mensah, Jubin; Mubarik, Yusif; Konadu, Peter; Ricchiuto, Arcangelo; Fimmers, Rolf; Arriens, Sandra; Dubben, Bettina; Ford, Louise; Taylor, Mark; Hoerauf, Achim

2017-01-01

The search for new macrofilaricidal drugs against onchocerciasis that can be administered in shorter regimens than required for doxycycline (DOX, 200mg/d given for 4–6 weeks), identified minocycline (MIN) with superior efficacy to DOX. Further reduction in the treatment regimen may be achieved with co-administration with standard anti-filarial drugs. Therefore a randomized, open-label, pilot trial was carried out in an area in Ghana endemic for onchocerciasis, comprising 5 different regimens: the standard regimen DOX 200mg/d for 4 weeks (DOX 4w, N = 33), the experimental regimens MIN 200mg/d for 3 weeks (MIN 3w; N = 30), DOX 200mg/d for 3 weeks plus albendazole (ALB) 800mg/d for 3 days (DOX 3w + ALB 3d, N = 32), DOX 200mg/d for 3 weeks (DOX 3w, N = 31) and ALB 800mg for 3 days (ALB 3d, N = 30). Out of 158 randomized participants, 116 (74.4%) were present for the follow-up at 6 months of whom 99 participants (63.5%) followed the treatment per protocol and underwent surgery. Histological analysis of the adult worms in the extirpated nodules revealed absence of Wolbachia in 98.8% (DOX 4w), 81.4% (DOX 3w + ALB 3d), 72.7% (MIN 3w), 64.1% (DOX 3w) and 35.2% (ALB 3d) of the female worms. All 4 treatment regimens showed superiority to ALB 3d (p < 0.001, p < 0.001, p = 0.002, p = 0.008, respectively), which was confirmed by real-time PCR. Additionally, DOX 4w showed superiority to all other treatment arms. Furthermore DOX 4w and DOX 3w + ALB 3d showed a higher amount of female worms with degenerated embryogenesis compared to ALB 3d (p = 0.028, p = 0.042, respectively). These results confirm earlier studies that DOX 4w is sufficient for Wolbachia depletion and the desired parasitological effects. The data further suggest that there is an additive effect of ALB (3 days) on top of that of DOX alone, and that MIN shows a trend for stronger potency than DOX. These latter two results are preliminary and need confirmation in a fully randomized controlled phase 2 trial. Trial

Doxycycline Attenuates Leptospira-Induced IL-1β by Suppressing NLRP3 Inflammasome Priming

PubMed Central

Zhang, Wenlong; Xie, Xufeng; Wu, Dianjun; Jin, Xuemin; Liu, Runxia; Hu, Xiaoyu; Fu, Yunhe; Ding, Zhuang; Zhang, Naisheng; Cao, Yongguo

2017-01-01

Doxycycline (Dox), a semisynthetic antibiotic, has been reported to exert multiple immunomodulatory effects. Treatment with Dox has a satisfactory curative effect against leptospirosis. In addition to its antibacterial action, we supposed that Dox also modulated immune response in controlling leptospira infection. Using J774A.1 mouse macrophages, the effects of Dox on protein and mRNA levels of IL-1β and TNF-α were investigated after infection with live or sonicated Leptospira interrogans serovar Lai strain Lai (56601). Specifically, the level of IL-1β but not TNF-α was sharply decreased when treated with Dox in leptospira-infected macrophages. Western blot analysis showed that Dox suppressed the activation of leptospira-induced MAPK and NF-κB signaling pathways. Using NLRP3-deficient and NLRC4-deficient mice, the data showed that the expression of leptospira-induced IL-1β was mainly dependent on the presence of NLRP3 inflammasome in macrophages. Meanwhile, Dox suppressed leptospira-induced NLRP3 inflammasome priming with the upregulation of the Na/K-ATPase Pump β1 subunit. The inhibition effect of Dox on IL-1β was also conspicuous in cells with lipopolysaccharide and ATP stimulation. These results were confirmed in vivo, as peritoneal fluids of mice and organs of hamsters expressed less IL-1β after treatment of leptospiral infection with Dox. Our results indicated that Dox also modulated immune response to attenuate leptospira-induced IL-1β by suppressing p38, JNK, p65, and NLRP3 inflammasome priming. PMID:28791016

Structural and thermodynamic characterization of doxycycline/β-cyclodextrin supramolecular complex and its bacterial membrane interactions.

PubMed

Suárez, Diego F; Consuegra, Jessika; Trajano, Vivianne C; Gontijo, Sávio M L; Guimarães, Pedro P G; Cortés, Maria E; Denadai, Ângelo L; Sinisterra, Rubén D

2014-06-01

Doxycycline is a semi-synthetic antibiotic commonly used for the treatment of many aerobic and anaerobic bacteria. It inhibits the activity of matrix metalloproteinases (MMPs) and affects cell proliferation. In this study, the structural and thermodynamic parameters of free DOX and a DOX/βCD complex were investigated, as well as their interactions and effects on Staphylococcus aureus cells and cellular cytotoxicity. Complexation of DOX and βCD was confirmed to be an enthalpy- and entropy-driven process, and a low equilibrium constant was obtained. Treatment of S. aureus with higher concentrations of DOX or DOX/βCD resulted in an exponential decrease in S. aureus cell size, as well as a gradual neutralization of zeta potential. These thermodynamic profiles suggest that ion-pairing and hydrogen bonding interactions occur between DOX and the membrane of S. aureus. In addition, the adhesion of βCD to the cell membrane via hydrogen bonding is hypothesized to mediate a synergistic effect which accounts for the higher activity of DOX/βCD against S. aureus compared to pure DOX. Lower cytotoxicity and induction of osteoblast proliferation was also associated with DOX/βCD compared with free DOX. These promising findings demonstrate the potential for DOX/βCD to mediate antimicrobial activity at lower concentrations, and provides a strategy for the development of other antimicrobial formulations. Copyright © 2014. Published by Elsevier B.V.

Excitation energy transfer in europium chelate with doxycycline in the presence of a second ligand in micellar solutions of nonionic surfactants

NASA Astrophysics Data System (ADS)

Smirnova, T. D.; Shtykov, S. N.; Kochubei, V. I.; Khryachkova, E. S.

2011-01-01

The complexation of Eu3+ with doxycycline (DC) antibiotic in the presence of several second ligands and surfactant micelles of different types is studied by the spectrophotometric and luminescence methods. It is found that the efficiency of excitation energy transfer in Eu3+-DC chelate depends on the nature of the second ligand and surfactant micelles. Using thenoyltrifluoroacetone (TTA) as an example, it is shown that the second ligand additionally sensitizes the europium fluorescence, and the possibility of intermediate sensitization of DC and then of europium is shown by the example of 1,10-phenanthroline. In all cases, the excitation energy transfer efficiency was increased due to the so-called antenna effect. The decay kinetics of the sensitized fluorescence of the binary and mixed-ligand chelates in aqueous and micellar solutions of nonionic surfactants is studied and the relative quantum yields and lifetimes of fluorescence are determined.

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators.

PubMed

Schmidt, Kim E; Kuepper, Janina M; Schumak, Beatrix; Alferink, Judith; Hofmann, Andrea; Howland, Shanshan W; Rénia, Laurent; Limmer, Andreas; Specht, Sabine; Hoerauf, Achim

2018-01-01

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4-6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions.

Low concentrations of doxycycline attenuates FasL-induced apoptosis in HeLa cells.

PubMed

Yoon, Jung Mi; Koppula, Sushruta; Huh, Se Jong; Hur, Sun Jin; Kim, Chan Gil

2015-07-24

Doxycycline (DC) has been shown to possess non-antibiotic properties including Fas/Fas Ligand (FasL)-mediated apoptosis against several tumor types in the concentration range of 10-40 µg/mL. However, the effect of DC in apoptotic signaling at much low concentrations was not studied. The present study investigated the attenuation effect of low dose of DC on FasL-induced apoptosis in HeLa cell by the methods of MTT assay, fluorescence microscopy, DNA fragmentation, flow cytometry analysis, and western blotting. In the present findings we showed that low concentration of DC (<2.0 µg/mL) exhibited protective effects against FasL-induced apoptosis in HeLa cells. FasL treatment to HeLa cells resulted in a concentration-dependent induction of cell death, and treatment with low concentrations of DC (0.1-2 µg/mL) significantly (p < 0.001) attenuated the FasL-induced cell death as measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Further, the FasL-induced apoptotic features in HeLa cells, such as morphological changes, DNA fragmentation and cell cycle arrest was also inhibited by DC (0.5 µg/mL). Tetracycline and minocycline also showed similar anti-apoptotic effects but were not significant when compared to DC, tested at same concentrations. Further, DC (0.01-16 µg/mL) did not influence the hydrogen peroxide- or cisplatin-induced intrinsic apoptotic pathway in HeLa cells. Protein analysis using Western blotting confirmed that FasL-induced cleavage/activation of caspase-8 and caspase-3, were inhibited by DC treatment at low concentration (0.5 µg/mL). Considering the overall data, we report for the first time that DC exhibited anti-apoptotic effects at low concentrations in HeLa cells by inhibition of caspase activation via FasL-induced extrinsic pathway.

Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis?

PubMed

Yiğit, Umut; Kırzıoğlu, Fatma Yeşim; Uğuz, Abdülhadi Cihangir; Nazıroğlu, Mustafa; Özmen, Özlem

2017-09-01

Host modulation therapies (anti-inflammatory drugs, bone-stimulating agents, anti-proteinase etc.) target the inhibition or stabilization of tissue breakdown. The aim of the present study was to evaluate the effects of caffeic acid phenethyl ester (CAPE) and/or low dose doxycycline (LDD) administrations on alveolar bone loss (ABL), serum cytokines and gingival apoptosis, as well as the levels of oxidants and anti-oxidants in rats with ligature-induced periodontitis. The animals were randomly divided into five groups: Group C (periodontally healthy), Group PC (Periodontitis+CAPE), Group PD (Periodontitis+LDD), Group PCD (Periodontitis+CAPE+LDD), Group P (Periodontitis). Experimental periodontitis was induced for 14days. Levels of ABL, and the serum cytokines, interleukin (IL)-1 β, IL-6, tumor necrosis factor-α (TNF-α) and IL-10 were assessed as were the levels of the oxidants and anti-oxidants, malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase (GSH-Px), and levels of gingival apoptosis. The lowest ABL levels was evident in the PC group, among the experimental groups. There was also less inflammatory infiltration in the PC group than the PD group. IL-1β, IL-6, and IL-10 were lower in the PC group and higher in the P group in comparison to the levels in the other experiment groups. TNF-α levels in the PD group were higher than levels in the PC and PCD groups. The PC and PCD groups did not differ from the C group in regard to MDA levels. The highest GSH-Px level was found in the PC group. Gingival apoptosis in the PC group was not only lower than the PD and PCD groups, but also lower than in the C group. The present study suggests that CAPE has more anti-inflammatory, anti-oxidant and anti-apoptotic effects than LDD, with no additive benefits of a CAPE+LDD combination being evident in rats with periodontitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Simultaneous UHPLC-UV analysis of hydroxychloroquine, minocycline and doxycycline from serum samples for the therapeutic drug monitoring of Q fever and Whipple's disease.

PubMed

Armstrong, Nicholas; Richez, Magali; Raoult, Didier; Chabriere, Eric

2017-08-15

A fast UHPLC-UV method was developed for the simultaneous analysis of Hydroxychloroquine, Minocycline and Doxycycline drugs from 100μL of human serum samples. Serum samples were extracted by liquid-liquid extraction and injected into a phenyl hexyl reverse phase column. Compounds were separated using a mobile phase linear gradient and monitored by UV detection at 343nm. Chloroquine and Oxytetracycline were used as internal standards. Lower and upper limits of quantifications, as well as the other levels of calibration, were validated with acceptable accuracy (<15% deviation) and precision (<15% coefficient of variation) according to the European Medicines Agency guidelines. This new method enables cost and time reduction and was considered suitable for the clinical laboratory. It is the first published assay for the therapeutic drug monitoring of patients diagnosed with Q fever or Whipple's disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators

PubMed Central

Alferink, Judith; Hofmann, Andrea; Howland, Shanshan W.; Rénia, Laurent; Limmer, Andreas; Specht, Sabine; Hoerauf, Achim

2018-01-01

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4–6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions. PMID:29438386

Modeling the permeability of multiaxial electrospun poly(ε-caprolactone)-gelatin hybrid fibers for controlled doxycycline release.

PubMed

Khalf, Abdurizzagh; Madihally, Sundararajan V

2017-07-01

Recent advances in electrospinning allow the formation of multiple layers of micro and nanosize fibers to regulate drug/therapeutic agent release. Although there has been significant progress in fiber formation techniques and drug loading, fundamental models providing insights into controlling individual permeabilities is lacking. In this regard, we first explored forming coaxial hybrid fibers from hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic gelatin (GT) in three different configurations, and the release of hydrophilic doxycycline (Dox) at 37°C over five days. Triaxial fibers were also formed with a GT layer between PCL/GT layers. Fibers were analyzed for fiber thickness, matrix porosity and thickness, surface morphologies, internal structures, stability in hydrated condition, viability and attachment of human adipocyte stem cells (hASC). Formed fibers were 10-30μm in diameter. hASC were viable, and showed attachment. Various release profiles were obtained from these fibers based on the combination of the core and shell polymers over five days. Using fiber characteristics and release profiles from each configuration, we obtained the overall permeability using Fick's first law and then individual layer permeability using resistance in series model. Calculated overall permeability showed dependency on fiber thickness and partition coefficient of the drug in the region where it was loaded. Our modeling approach helps in optimizing the electrospinning process, drug loading, and polymer solution configuration in regulating controlled release of a drug. Copyright © 2017 Elsevier B.V. All rights reserved.

Chitosan-doxycycline hydrogel: An MMP inhibitor/sclerosing embolizing agent as a new approach to endoleak prevention and treatment after endovascular aneurysm repair.

PubMed

Zehtabi, Fatemeh; Ispas-Szabo, Pompilia; Djerir, Djahida; Sivakumaran, Lojan; Annabi, Borhane; Soulez, Gilles; Mateescu, Mircea Alexandru; Lerouge, Sophie

2017-12-01

The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)-a sclerosant and MMP inhibitor-was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX

Construction of doxycycline-mediated BMP-2 transgene combining with APA microcapsules for bone repair.

PubMed

Qian, Dongyang; Bai, Bo; Yan, Guangbin; Zhang, Shujiang; Liu, Qi; Chen, Yi; Tan, Xiaobo; Zeng, Yanjun

2016-01-01

The repairing of large segmental bone defects is difficult for clinical orthopedists at present. Gene therapy is regarded as a promising method for bone defects repair. The present study aimed to construct an effective and controllable Tet-On expression system for transferring hBMP-2 gene into bone marrow mesenchymal progenitor cells (BMSCs). Meanwhile, with combination of alginate-poly-L-lysine-alginate (APA) microencapsulation technology, we attempted to reduce the influence of immunologic rejection and examine the effect of the Tet-On expression system on osteogenesis of BMSCs. The adenovirus encoding hBMP-2 (ADV-hBMP2) was constructed using the means of molecular cloning. The ADV-hBMP2 and Adeno-X Tet-On virus was respectively transfected to the HEK293 for amplification and afterward BMSCs were co-infected with the virus of ADV-hBMP2 and the Adeno-X Tet-On. The expression of hBMP-2 was measured with induction by doxycycline (DOX) at different concentration by means of RT-PCR and ELISA. Combining Tet-On expression system and APA microcapsules with the use of the pulsed high-voltage electrostatic microcapsule instrument, we examined the expression level of hBMP-2 in APA microcapsules by ELISA as well as the osteogenesis by alizarin red S staining. An effective Tet-On expression system for transferring hBMP-2 gene into BMSCs was constructed successfully. Also, the expression of hBMP-2 could be regulated by concentration of DOX. The data exhibited that BMSCs in APA microcapsules maintained the capability of proliferation and differentiation. The combination of Tet-On expression system and APA microcapsules could promote the osteogenesis of BMSCs. According to the results, microencapsulated Tet-On expression system showed the effective characteristics of secreting hBMP-2 and enhancing osteogenesis, which would provide a promising way for bone repair.

Therapeutic Effects of Doxycycline on the Quality of Repaired and Unrepaired Achilles Tendons.

PubMed

Nguyen, Quynhhoa T; Norelli, Jolanta B; Graver, Adam; Ekstein, Charles; Schwartz, Johnathan; Chowdhury, Farzana; Drakos, Mark C; Grande, Daniel A; Chahine, Nadeen O

2017-10-01

Achilles tendon tears are devastating injuries, especially to athletes. Elevated matrix metalloproteinase (MMP) activity after a tendon injury has been associated with deterioration of the collagen network and can be inhibited with doxycycline (Doxy). Daily oral administration of Doxy will enhance the histological, molecular, and biomechanical quality of transected Achilles tendons. Additionally, suture repair will further enhance the quality of repaired tendons. Controlled laboratory study. Randomized unilateral Achilles tendon transection was performed in 288 adult male Sprague-Dawley rats. The injured tendons were either unrepaired (groups 1 and 2) or surgically repaired (groups 3 and 4). Animals from groups 2 and 4 received Doxy daily through oral gavage, and animals from groups 1 and 3 served as controls (no Doxy). Tendons were harvested at 1.5, 3, 6, and 9 weeks after the injury (n = 18 per group and time point). The quality of tendon repair was evaluated based on the histological grading score, collagen fiber orientation, gene expression, and biomechanical properties. In surgically repaired samples, Doxy enhanced the quality of tendon repair compared with no Doxy ( P = .0014). Doxy had a significant effect on collagen fiber dispersion, but not principal fiber angle. There was a significant effect of time on the gene expression of MMP-3, MMP-9 and TIMP1, and Doxy significantly decreased MMP-3 expression at 9 weeks. Doxy treatment with surgical repair increased the dynamic modulus at 6 weeks but not at 9 weeks after the injury ( P < .001). Doxy also increased the equilibrium modulus and decreased creep strain irrespective of the repair group. Doxy did not have a significant effect on the histology or biomechanics of unrepaired tendons. The findings indicate that daily oral administration of Doxy accelerated matrix remodeling and the dynamic and equilibrium biomechanics of surgically repaired Achilles tendons, although such enhancements were most evident at the

Effect of citric acid, tetracycline, and doxycycline on instrumented periodontally involved root surfaces: A SEM study

PubMed Central

Chahal, Gurparkash Singh; Chhina, Kamalpreet; Chhabra, Vipin; Bhatnagar, Rakhi; Chahal, Amna

2014-01-01

Background: A surface smear layer consisting of organic and inorganic material is formed on the root surface following mechanical instrumentation and may inhibit the formation of new connective tissue attachment to the root surface. Modification of the tooth surface by root conditioning has resulted in improved connective tissue attachment and has advanced the goal of reconstructive periodontal treatment. Aim: The aim of this study was to compare the effects of citric acid, tetracycline, and doxycycline on the instrumented periodontally involved root surfaces in vitro using a scanning electron microscope. Settings and Design: A total of 45 dentin samples obtained from 15 extracted, scaled, and root planed teeth were divided into three groups. Materials and Methods: The root conditioning agents were applied with cotton pellets using the Passive burnishing technique for 5 minutes. The samples were then examined by the scanning electron microscope. Statistical Analysis Used: The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 15.0 for Windows). For all quantitative variables means and standard deviations were calculated and compared. For more than two groups ANOVA was applied. For multiple comparisons post hoc tests with Bonferroni correction was used. Results: Upon statistical analysis the root conditioning agents used in this study were found to be effective in removing the smear layer, uncovering and widening the dentin tubules and unmasking the dentin collagen matrix. Conclusion: Tetracycline HCl was found to be the best root conditioner among the three agents used. PMID:24744541

A doxycycline-dependent human immunodeficiency virus type 1 replicates in vivo without inducing CD4+ T-cell depletion

PubMed Central

Legrand, Nicolas; van der Velden, Gisela J.; Fang, Raphaël Ho Tsong; Douaisi, Marc; Weijer, Kees; Das, Atze T.; Blom, Bianca; Uittenbogaart, Christel H.; Berkhout, Ben

2012-01-01

A novel genetic approach for the control of virus replication was used for the design of a conditionally replicating human immunodeficiency virus (HIV) variant, HIV-rtTA. HIV-rtTA gene expression and virus replication are strictly dependent on the presence of a non-toxic effector molecule, doxycycline (dox), and thus can be turned on and off at will in a graded and reversible manner. The in vivo replication capacity, pathogenicity and genetic stability of this HIV-rtTA variant were evaluated in a humanized mouse model of haematopoiesis that harbours lymphoid and myeloid components of the human immune system (HIS). Infection of dox-fed BALB Rag/γc HIS (BRG-HIS) mice with HIV-rtTA led to the establishment of a productive infection without CD4+ T-cell depletion. The virus did not show any sign of escape from dox control for up to 10 weeks after the onset of infection. No reversion towards a functional Tat–transactivating responsive (TAR) RNA element axis was observed, confirming the genetic stability of the HIV-rtTA variant in vivo. These results demonstrate the proof of concept that HIV-rtTA replicates efficiently in vivo. HIV-rtTA is a promising tool for fundamental research to study virus–host interactions in vivo in a controlled fashion. PMID:22647372

Effects of doxycycline on serum and endometrial levels of MMP-2, MMP-9 and TIMP-1 in women using a levonorgestrel-releasing subcutaneous implant.

PubMed

Zhao, Shumei; Choksuchat, Chainarong; Zhao, Yueqin; Ballagh, Susan A; Kovalevsky, George A; Archer, David F

2009-06-01

Endometrial spotting and/or bleeding (ESB) occurs in levonorgestrel subcutaneous implant (LNG SI) users. Matrix metalloproteinases (MMPs) may play a role in ESB. Women between 18 and 40 years with regular menstrual cycles had a baseline evaluation followed by LNG SI insertion and randomization to doxycycline (DOX; 20 mg) or placebo (PL) twice a day. MMP-2, MMP-9 and tissue inhibitor of MMP-1 (TIMP-1) in serum and the endometrium were estimated at baseline and at 1, 3 and 6 months after insertion. LNG increased serum MMP-9, while DOX decreased MMP-9 levels compared to PL after 1 month (p<.05). DOX decreased endometrial MMP-9 at 1 and 6 months compared to baseline and PL (p<.05). DOX increased endometrial TIMP-1 at 6 months compared with baseline and PL (p<.05). MMP-2 levels were unchanged. LNG SI increased serum MMP-9 and TIMP-1 levels, while DOX decreased both serum and endometrial MMP-9 levels.

Doxycycline-containing glass ionomer cement for arresting residual caries: an in vitro study and a pilot trial

PubMed Central

Duque, Cristiane; Kreling, Paula Fernanda; Pereira, Jesse Augusto; de Paula, Andreia Bolzan; Sinhoreti, Mario Alexandre Coelho; Puppin-Rontani, Regina Maria

2018-01-01

Abstract In a previous study, we demonstrated that the incorporation of doxycycline hyclate (DOX) into resin-modified glass ionomer cement (RMGIC) inhibited important cariogenic microorganisms, without modifying its biological and mechanical characteristics. In this study, we keep focused on the effect of that experimental material as a potential therapy for arresting residual caries by analyzing other in vitro properties and conducting a pilot clinical trial assessing the in vivo effect of DOX-containing RMGIC on residual mutans streptococci after partial carious removal in primary molars. Specimens of the groups RMGIC (control); RMGIC + 1.5% DOX; RMGIC + 3% DOX; and RMGIC + 4.5% DOX were made to evaluate the effect of DOX incorporation on surface microhardness and fluoride release of RMGIC and against biofilm of Streptococcus mutans. Clinical intervention consisted of partial caries removal comparing RMGIC and RMGIC + 4.5% DOX as lining materials. After 3 months, clinical and microbiologic evaluations were performed. Data were submitted to ANOVA/Tukey or Wilcoxon/Mann-Whitney set as α=0.05. Fluoride release and surface microhardness was not influenced by the incorporation of DOX (p>0.05). There was a significant reduction of S. mutans biofilm over the material surface with the increase of DOX concentration. After clinical trial, the remaining dentin was hard and dry. Additionally, mutans streptococci were completely eliminated after 3 months of treatment with RMGIC + 4.5% DOX. The incorporation of DOX provided better antibiofilm effect, without jeopardizing fluoride release and surface microhardness of RMGIC. This combination also improved the in vivo shortterm microbiological effect of RMGIC after partial caries removal. PMID:29742263

Doxycycline-containing glass ionomer cement for arresting residual caries: an in vitro study and a pilot trial.

PubMed

Castilho, Aline Rogéria Freire de; Duque, Cristiane; Kreling, Paula Fernanda; Pereira, Jesse Augusto; Paula, Andreia Bolzan de; Sinhoreti, Mario Alexandre Coelho; Puppin-Rontani, Regina Maria

2018-01-01

In a previous study, we demonstrated that the incorporation of doxycycline hyclate (DOX) into resin-modified glass ionomer cement (RMGIC) inhibited important cariogenic microorganisms, without modifying its biological and mechanical characteristics. In this study, we keep focused on the effect of that experimental material as a potential therapy for arresting residual caries by analyzing other in vitro properties and conducting a pilot clinical trial assessing the in vivo effect of DOX-containing RMGIC on residual mutans streptococci after partial carious removal in primary molars. Specimens of the groups RMGIC (control); RMGIC + 1.5% DOX; RMGIC + 3% DOX; and RMGIC + 4.5% DOX were made to evaluate the effect of DOX incorporation on surface microhardness and fluoride release of RMGIC and against biofilm of Streptococcus mutans. Clinical intervention consisted of partial caries removal comparing RMGIC and RMGIC + 4.5% DOX as lining materials. After 3 months, clinical and microbiologic evaluations were performed. Data were submitted to ANOVA/Tukey or Wilcoxon/Mann-Whitney set as α=0.05. Fluoride release and surface microhardness was not influenced by the incorporation of DOX (p>0.05). There was a significant reduction of S. mutans biofilm over the material surface with the increase of DOX concentration. After clinical trial, the remaining dentin was hard and dry. Additionally, mutans streptococci were completely eliminated after 3 months of treatment with RMGIC + 4.5% DOX. The incorporation of DOX provided better antibiofilm effect, without jeopardizing fluoride release and surface microhardness of RMGIC. This combination also improved the in vivo shortterm microbiological effect of RMGIC after partial caries removal.

Soil texture-depending effects of doxycycline and streptomycin applied with manure on the bacterial community composition and resistome.

PubMed

Blau, Khald; Casadevall, Laia; Wolters, Birgit; Van den Meersche, Tina; Kreuzig, Robert; Smalla, Kornelia; Jechalke, Sven

2018-02-01

Veterinary antibiotics, bacteria carrying antibiotic resistance determinants located on mobile genetic elements and nutrients are spread on agricultural soil using manure as fertilizer. However, systematic quantitative studies linking antibiotic concentrations and antimicrobial resistance genes (ARGs) in manure and the environment are scarce but needed to assess environmental risks. In this microcosm study, a sandy and a loamy soil were mixed with manure spiked with streptomycin or doxycycline at five concentrations. Total-community DNA was extracted on days 28 and 92, and the abundances of ARGs (aadA, strA, tet(A), tet(M), tet(W), tet(Q), sul1, qacE/qacEΔ1) and class 1 and 2 integron integrase genes (intI1 and intI2) were determined by qPCR relative to 16S rRNA genes. Effects on the bacterial community composition were evaluated by denaturing gradient gel electrophoresis of 16S rRNA gene amplicons. Manure application to the soils strongly increased the relative abundance of most tested genes. Antibiotics caused further enrichments which decreased over time and were mostly seen at high concentrations. Strikingly, the effects on relative gene abundances and soil bacterial community composition were more pronounced in sandy soil. The concept of defining antibiotic threshold concentrations for environmental risk assessments remains challenging due to the various influencing factors. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A multicenter study of topical azelaic acid 15% gel in combination with oral doxycycline as initial therapy and azelaic acid 15% gel as maintenance monotherapy.

PubMed

Thiboutot, Diane M; Fleischer, Alan B; Del Rosso, James Q; Rich, Phoebe

2009-07-01

This two-phase, multicenter study was undertaken to examine the safety and efficacy of combination therapy with oral doxycycline and topical azelaic acid (AzA) 15% gel in moderate-to-severe papulopustular rosacea and to determine the effect of subsequent maintenance monotherapy with AzA 15% gel alone. In the initial open-label, non-randomized phase of the study, subjects (n=172) received topical AzA 15% gel and oral doxycycline (100 mg), both twice daily, for < or = 12 weeks. In the second, double-blind study phase, subjects who had initially undergone at least four weeks of combination treatment in phase 1 and who achieved > or = 75% inflammatory lesion count reduction (n=136) were randomized to receive either AzA 15% gel or its vehicle twice daily for an additional 24 weeks. Assessments of efficacy were obtained at four-week intervals throughout both phases of the study and included change in inflammatory lesion count, investigator global assessment (IGA) of rosacea severity, and separate assessments of erythema and telangiectasia severity. At the last visit for each phase of the study, the investigator and participant each rated overall improvement, with the participant rating cosmetic acceptability and the investigator rating treatment as "success" or "failure" based on IGA score. During the second phase of the trial, the rate of relapse -- defined as either a 50% deterioration in the lesion count improvement from phase 1, an increase in erythema intolerable to the subject or maintenance therapy failure as judged by the investigator and/or the subject -- was obtained. Safety assessments were conducted for both phases of the study and included analysis of adverse events (AEs) and a rating of cutaneous tolerability by the subject. By week 12 of the open-label phase of the study, 81.4% of subjects had reached a 75% or greater reduction in inflammatory lesion count, and 64% of patients achieved treatment success. During the second study phase (maintenance phase

Preparation of antibodies and development of an enzyme-linked immunosorbent assay (ELISA) for the determination of doxycycline antibiotic in milk samples.

PubMed

Adrian, Javier; Fernández, Fátima; Sánchez-Baeza, Francisco; Marco, M-Pilar

2012-04-18

This paper reports the development of an immunoassay for the specific analysis of doxycycline (DC), a congener of the tetracycline antibiotic family (TCs), in milk samples. This is the first time that DC antibody production is reported, based on a rationally designed and well-characterized immunizing hapten. The chemical structure of the immunizing hapten (13-[(2-carboxyethyl)thiol]-5-hydroxy-6-α-deoxytetracycline, TC1) was designed to maximize recognition of the tetracycline characteristic moiety defined as lower periphery of the TCs plus the region of the upper periphery composed by the hydroxyl group at position C(5) (B ring) and the dimethylamino group in ring A. Polyclonal antibodies raised against TC1 coupled to horseshoe crab hemocianyn (HCH) were used to develop a homologous indirect competitive enzyme-linked immunosorbent assay (ELISA). The microplate ELISA can detect DC in buffer down to 0.1 μg L(-1). The ELISA has been proven to tolerate a wide range of ionic strengths and pH values. The assay is very selective for DC with a minor recognition of methacycline (32% of cross-reactivity). Experiments performed with whole milk samples demonstrate that samples can be directly analyzed after a simple treatment method, reaching detectability values below 5 μg L(-1).

Residues of chlortetracycline, doxycycline and sulfadiazine-trimethoprim in intestinal content and feces of pigs due to cross-contamination of feed.

PubMed

Peeters, Laura E J; Daeseleire, Els; Devreese, Mathias; Rasschaert, Geertrui; Smet, Annemieke; Dewulf, Jeroen; Heyndrickx, Marc; Imberechts, Hein; Haesebrouck, Freddy; Butaye, Patrick; Croubels, Siska

2016-09-20

Cross-contamination of feed with low concentrations of antimicrobials can occur at production, transport and/or farm level. Concerns are rising about possible effects of this contaminated feed on resistance selection in the intestinal microbiota. Therefore, an experiment with pigs was set up, in which intestinal and fecal concentrations of chlortetracycline (CTC), doxycycline (DOX) and sulfadiazine-trimethoprim (SDZ-TRIM) were determined after administration of feed containing a 3 % carry-over level of these antimicrobials. The poor oral bioavailability of tetracyclines resulted in rather high concentrations in cecal and colonic content and feces at steady-state conditions. A mean concentration of 10 mg/kg CTC and 4 mg/kg DOX in the feces was reached, which is higher than concentrations that were shown to cause resistance selection. On the other hand, lower mean levels of SDZ (0.7 mg/kg) and TRIM (< limit of detection of 0.016 mg/kg) were found in the feces, corresponding with the high oral bioavailability of SDZ and TRIM in pigs. The relation between the oral bioavailability and intestinal concentrations of the tested antimicrobials, may be of help in assessing the risks of cross-contaminated feed. However, future research is needed to confirm our results and to evaluate the effects of these detected concentrations on resistance selection in the intestinal microbiota of pigs.

Doxycycline

MedlinePlus

... a serious infection that may be spread on purpose as part of a bioterror attack), in people ... tuleramia (serious infections that may be spread on purpose as part of a bioterror attack). It is ...

Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: prevent seeds from gemmating on soil

PubMed Central

Xu, Huo; Ma, Ji; Zhu, Yewei; Lu, Yusheng; Wang, Jichuang; Zhang, Ting; Li, Tao; Xie, Jingjing; Xu, Bo; Xie, Fangwei; Gao, Yu; Shao, Jingwei; Tu, Xiaohuang; Jia, Lee

2015-01-01

Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity. PMID:26459390

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pomorska-Mól, Małgorzata, E-mail: mpomorska@piwet.pulawy.pl; Kwit, Krzysztof; Markowska-Daniel, Iwona

The effect of a seven-day antibiotic therapy with doxycycline was investigated on the postvaccinal humoral and cellular immune response in pigs. The selected parameters of non-specific immunity were also studied. Fifty pigs were used (control not vaccinated (C, n = 10), control vaccinated (CV, n = 20), and experimental — received doxycycline (DOXY, n = 20)). For vaccination live-attenuated vaccine against pseudorabies (PR) was used. From day − 1 to day 5 pigs from DOXY group received doxycycline orally with drinking water, at the recommended dose. Pigs from DOXY and CV groups were vaccinated at 8 and 10 weeks ofmore » age. The results of the present study showed that cell-mediated postvaccinal immune response can be modulated by oral treatment with doxycycline. Significantly lower values of stimulation index were observed after PRV restimulation in doxycycline-treated pigs. Moreover, in the DOXY group a significant decrease in IFN-γ production after PRV restimulation was noted. The significantly lower number of CD4+CD8 + cells was also observed in doxy-treated, vaccinated pigs, 2 weeks after final vaccination. Simultaneously, specific humoral response was not disturbed. This study demonstrated the importance of defining the immune modulatory activity of doxycycline because it may alter the immune responses to vaccines. The exact mechanism of T-cell response suppression by doxycycline remains to be elucidated, however the influence of doxycycline on the secretion of various cytokines, including IFN-γ, may be considered as a possible cause. The present observations should prompt further studies on the practical significance of such phenomena in terms of clinical implications. - Highlights: • We examine the postvaccinal immune response in pigs treated with doxycycline. • Doxycycline negatively influenced the specific proliferation after recall stimulation. • Doxycycline negatively influenced secretion of IFN-γ after recall stimulation. • The lower

DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line.

PubMed

Fares, Mona; Abedi-Valugerdi, Manuchehr; Hassan, Moustapha; Potácová, Zuzana

2015-07-31

We investigated mechanisms of cytotoxicity induced by doxycycline (doxy) and minocycline (mino) in the chronic myeloid leukemia K562 cell line. Doxy and mino induced cell death in exposure-dependent manner. While annexin V/propidium iodide staining was consistent with apoptosis, the morphological changes in Giemsa staining were more equivocal. A pancaspase inhibitor Z-VAD-FMK partially reverted cell death morphology, but concurrently completely prevented PARP cleavage. Mitochondrial involvement was detected as dissipation of mitochondrial membrane potential and cytochrome C release. DNA double strand breaks detected with γH2AX antibody and caspase-2 activation were found early after the treatment start, but caspase-3 activation was a late event. Decrement of Bcl-xL protein levels and electrophoretic shift of Bcl-xL molecule were induced by both drugs. Phosphorylation of Bcl-xL at serine 62 was ruled out. Similarly, Bcr/Abl tyrosine kinase levels were decreased. Lysosomal inhibitor chloroquine restored Bcl-xL and Bcr/Abl protein levels and inhibited caspase-3 activation. Thus, the cytotoxicity of doxy and mino in K562 cells is mediated by DNA damage, Bcl-xL deamidation and lysosomal degradation with activation of mitochondrial pathway of apoptosis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

No evidential correlation between veterinary antibiotic degradation ability and resistance genes in microorganisms during the biodegradation of doxycycline.

PubMed

Wen, Xin; Wang, Yan; Zou, Yongde; Ma, Baohua; Wu, Yinbao

2018-01-01

Biodegradation of antibiotic residues in the environment by microorganisms may lead to the generation of antibiotic resistance genes (ARGs), which are of great concern to human health. The aim of this study was to determine whether there is a relationship between the ability to degrade antibiotic doxycycline (DOX) and the development of resistance genes in microorganisms. We isolated and identified ten bacterial strains from a vegetable field that had received long-term manure application as fertilizer and were capable of surviving in a series of DOX concentrations (25, 50, 80, and 100mg/L). Our results showed no evidential correlation between DOX degradation ability and the development of resistance genes among the isolated microorganisms that had high DOX degradation capability (P > 0.05). This was based on the fact that Escherichia sp. and Candida sp. were the most efficient bacterial strains to degrade DOX (92.52% and 91.63%, respectively), but their tetracycline resistance genes showed a relatively low risk of antibiotic resistance in a 7-day experiment. Moreover, the tetM of the ribosomal protection protein genes carried by these two preponderant bacteria was five-fold higher than that carried by other isolates (P < 0.05). Pearson correlations between the C t /C 0 of DOX and tet resistance genes of three isolates, except for Escherichia sp. and Candida sp., showed remarkable negative correlations (P < 0.05), mainly because tetG markedly increased during the DOX degradation process. Our results concluded that the biodegradation of antibiotic residues may not necessarily lead to the development of ARGs in the environment. In addition, the two bacteria that we isolated, namely, Escherichia sp. and Candida sp., are potential candidates for the engineering of environmentally friendly bacteria. Copyright © 2017 Elsevier Inc. All rights reserved.

A novel approach to the use of doxycycline-loaded biodegradable membrane and EDTA root surface etching in chronic periodontitis: a randomized clinical trial.

PubMed

Gamal, Ahmed Y; Kumper, Radi M

2012-09-01

The release profile of 25% doxycycline (DOX) gel loaded on a biodegradable collagen membrane (COL) after 24% EDTA root surface etching was evaluated. Thirty systemically healthy patients, each with at least one pair of contralateral interproximal intrabony defects ≥4 mm deep, along with an interproximal probing depth ≥6 mm and clinical attachment loss ≥4 mm, were randomized into two groups. Group 1 consisted of sites treated with open-flap debridement followed by placement of DOX gel-loaded COL (DOX-COL), whereas group 2 sites were treated with flap surgery followed by the placement of DOX-COL after EDTA etching of the exposed root surfaces (DOX-COL + EDTA). Samples of gingival crevicular fluid were obtained 1, 3, 7, 14, and 21 days after surgery. Separation was performed, and quantitative measurements of DOX were taken with a high-performance liquid chromatography. Clinical evaluation and follow-up for 6 months were performed. At 21 days, DOX-COL + EDTA group showed 5.3 μg/mL value. However, no DOX was detected in samples of the DOX-COL group. DOX-COL + EDTA-treated group retained more DOX during the periods of 3, 7, 10, and 14 days than did the DOX-COL group. EDTA root surface etching could enhance DOX availability in the gingival crevicular fluid after its release from the collagen membrane.

Systematic Review and Meta-Analysis of Randomized Clinical Trials in the Treatment of Human Brucellosis

PubMed Central

Solís García del Pozo, Julián; Solera, Javier

2012-01-01

Background Brucellosis is a persistent health problem in many developing countries throughout the world, and the search for simple and effective treatment continues to be of great importance. Methods and Findings A search was conducted in MEDLINE and in the Cochrane Central Register of Controlled Trials (CENTRAL). Clinical trials published from 1985 to present that assess different antimicrobial regimens in cases of documented acute uncomplicated human brucellosis were included. The primary outcomes were relapse, therapeutic failure, combined variable of relapse and therapeutic failure, and adverse effect rates. A meta-analysis with a fixed effect model was performed and odds ratio with 95% confidence intervals were calculated. A random effect model was used when significant heterogeneity between studies was verified. Comparison of combined doxycycline and rifampicin with a combination of doxycycline and streptomycin favors the latter regimen (OR = 3.17; CI95% = 2.05–4.91). There were no significant differences between combined doxycycline-streptomycin and combined doxycycline-gentamicin (OR = 1.89; CI95% = 0.81–4.39). Treatment with rifampicin and quinolones was similar to combined doxycycline-rifampicin (OR = 1.23; CI95% = 0.63–2.40). Only one study assessed triple therapy with aminoglycoside-doxycycline-rifampicin and only included patients with uncomplicated brucellosis. Thus this approach cannot be considered the therapy of choice until further studies have been performed. Combined doxycycline/co-trimoxazole or doxycycline monotherapy could represent a cost-effective alternative in certain patient groups, and further studies are needed in the future. Conclusions Although the preferred treatment in uncomplicated human brucellosis is doxycycline-aminoglycoside combination, other treatments based on oral regimens or monotherapy should not be rejected until they are better studied. Triple therapy should not be considered the current

Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming and Can Be Used to Identify the Critical Timing of Transgene Expression.

PubMed

Umei, Tomohiko C; Yamakawa, Hiroyuki; Muraoka, Naoto; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Kurotsu, Shota; Tamura, Fumiya; Osakabe, Rina; Tani, Hidenori; Nara, Kaori; Miyoshi, Hiroyuki; Fukuda, Keiichi; Ieda, Masaki

2017-08-19

Direct reprogramming is a promising approach in regenerative medicine. Overexpression of the cardiac transcription factors Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2 (GHMT) directly reprogram fibroblasts into cardiomyocyte-like cells (iCMs). However, the critical timing of transgene expression and the molecular mechanisms for cardiac reprogramming remain unclear. The conventional doxycycline (Dox)-inducible temporal transgene expression systems require simultaneous transduction of two vectors (pLVX-rtTA/pLVX-cDNA) harboring the reverse tetracycline transactivator (rtTA) and the tetracycline response element (TRE)-controlled transgene, respectively, leading to inefficient cardiac reprogramming. Herein, we developed a single-construct-based polycistronic Dox-inducible vector (pDox-cDNA) expressing both the rtTA and TRE-controlled transgenes. Fluorescence activated cell sorting (FACS) analyses, quantitative RT-PCR, and immunostaining revealed that pDox-GMT increased cardiac reprogramming three-fold compared to the conventional pLVX-rtTA/pLVX-GMT. After four weeks, pDox-GMT-induced iCMs expressed multiple cardiac genes, produced sarcomeric structures, and beat spontaneously. Co-transduction of pDox-Hand2 with retroviral pMX-GMT increased cardiac reprogramming three-fold compared to pMX-GMT alone. Temporal Dox administration revealed that Hand2 transgene expression is critical during the first two weeks of cardiac reprogramming. Microarray analyses demonstrated that Hand2 represses cell cycle-promoting genes and enhances cardiac reprogramming. Thus, we have developed an efficient temporal transgene expression system, which could be invaluable in the study of cardiac reprogramming.

Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming and Can Be Used to Identify the Critical Timing of Transgene Expression

PubMed Central

Umei, Tomohiko C.; Yamakawa, Hiroyuki; Muraoka, Naoto; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Kurotsu, Shota; Tamura, Fumiya; Osakabe, Rina; Tani, Hidenori; Nara, Kaori; Miyoshi, Hiroyuki; Fukuda, Keiichi; Ieda, Masaki

2017-01-01

Direct reprogramming is a promising approach in regenerative medicine. Overexpression of the cardiac transcription factors Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2 (GHMT) directly reprogram fibroblasts into cardiomyocyte-like cells (iCMs). However, the critical timing of transgene expression and the molecular mechanisms for cardiac reprogramming remain unclear. The conventional doxycycline (Dox)-inducible temporal transgene expression systems require simultaneous transduction of two vectors (pLVX-rtTA/pLVX-cDNA) harboring the reverse tetracycline transactivator (rtTA) and the tetracycline response element (TRE)-controlled transgene, respectively, leading to inefficient cardiac reprogramming. Herein, we developed a single-construct-based polycistronic Dox-inducible vector (pDox-cDNA) expressing both the rtTA and TRE-controlled transgenes. Fluorescence activated cell sorting (FACS) analyses, quantitative RT-PCR, and immunostaining revealed that pDox-GMT increased cardiac reprogramming three-fold compared to the conventional pLVX-rtTA/pLVX-GMT. After four weeks, pDox-GMT-induced iCMs expressed multiple cardiac genes, produced sarcomeric structures, and beat spontaneously. Co-transduction of pDox-Hand2 with retroviral pMX-GMT increased cardiac reprogramming three-fold compared to pMX-GMT alone. Temporal Dox administration revealed that Hand2 transgene expression is critical during the first two weeks of cardiac reprogramming. Microarray analyses demonstrated that Hand2 represses cell cycle-promoting genes and enhances cardiac reprogramming. Thus, we have developed an efficient temporal transgene expression system, which could be invaluable in the study of cardiac reprogramming. PMID:28825623

Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis.

PubMed

Penna, Pete; Meckfessel, Matthew H; Preston, Norman

2014-01-01

Acne vulgaris is a chronic skin disease with a high prevalence. Left untreated or inadequately treated, acne vulgaris can lead to psychological and physical scarring, as well as to unnecessary medical expenses. Oral isotretinoin is an effective treatment for severe resistant nodular and conglobate acne vulgaris. A regimen consisting of a fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO) with oral doxycycline 100 mg (A-BPO/D) has been demonstrated to be efficacious and well tolerated in patients with severe acne and may be an alternative to oral isotretinoin for some patients with severe acne. The objective of this analysis was to compare the relative efficacy and associated costs of A-BPO/D versus oral isotretinoin. In this analysis, comparisons of relative efficacy were made using previously published studies involving similar patient populations with severe acne that warrant the use of oral isotretinoin. The pricing for oral doxycycline and oral isotretinoin was estimated based on the maximum allowable cost from 9 states, and the pricing for A-BPO was calculated as the range between the average wholesale price and the wholesale acquisition cost. For this analysis, 2 treatment models were generated to compare costs: (1) a basic treatment model that examined the costs of an initial regimen of either A-BPO/D or oral isotretinoin without considering probable outcomes, and (2) a long-term model that factored in likely treatment outcomes and subsequent treatments into associated costs. The basic treatment model assumed that patients would be prescribed a single regimen of A-BPO/D for 12 weeks or oral isotretinoin for 20 weeks. The long-term model considered the probability of each treatment successfully managing patients' acne, as well as likely additional regimens of A-BPO monotherapy or an additional regimen of oral isotretinoin. As a result of different treatment durations, the costs for each treatment were normalized to weekly cost of

A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimura, Nao; Endo, Shinya; Ueno, Shikiko

We previously demonstrated that PU.1 expression is down-regulated in the majority of myeloma cell lines and primary myeloma cells from patients. We introduced the tet-off system into the human myeloma cell lines U266 and KMS12PE that conditionally express PU.1 and demonstrated that PU.1 induces cell cycle arrest and apoptosis in myeloma cells in vitro. Here, we established a mouse xenograft model of myeloma using these cell lines to analyze the effects of PU.1 on the phenotype of myeloma cells in vivo. When doxycycline was added to the drinking water of mice engrafted with these myeloma cells, all mice had continuous growth ofmore » subcutaneous tumors and could not survived more than 65 days. In contrast, mice that were not exposed to doxycycline did not develop subcutaneous tumors and survived for at least 100 days. We next generated mice engrafted with subcutaneous tumors 5–10 mm in diameter that were induced by exposure to doxycycline. Half of the mice stopped taking doxycycline-containing water, whereas the other half kept taking the water. Although the tumors in the mice taking doxycycline continued to grow, tumor growth in the mice not taking doxycycline was significantly suppressed. The myeloma cells in the tumors of the mice not taking doxycycline expressed PU.1 and TRAIL and many of such cells were apoptotic. Moreover, the expression of a cell proliferation marker Ki67 was significantly decreased in tumors from the mice not taking doxycycline, compared with that of tumors from the mice continuously taking doxycycline. The present data strongly suggest that PU.1 functions as a tumor suppressor of myeloma cells in vivo. - Highlights: • PU.1 suppresses xenograft myeloma cell growth and prolongs survival periods of mice. • PU.1 induces TRAIL expression and apoptosis in myeloma cells in vivo. • PU.1 suppresses Ki67 expression in myeloma cells in vivo. • Up-regulation of PU.1 is a promising strategy for generating anti-myeloma agents.« less

The Development of a Viral Mediated CRISPR/Cas9 System with Doxycycline Dependent gRNA Expression for Inducible In vitro and In vivo Genome Editing

PubMed Central

de Solis, Christopher A.; Ho, Anthony; Holehonnur, Roopashri; Ploski, Jonathan E.

2016-01-01

The RNA-guided Cas9 nuclease, from the type II prokaryotic Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) adaptive immune system, has been adapted and utilized by scientists to edit the genomes of eukaryotic cells. Here, we report the development of a viral mediated CRISPR/Cas9 system that can be rendered inducible utilizing doxycycline (Dox) and can be delivered to cells in vitro and in vivo utilizing adeno-associated virus (AAV). Specifically, we developed an inducible gRNA (gRNAi) AAV vector that is designed to express the gRNA from a H1/TO promoter. This AAV vector is also designed to express the Tet repressor (TetR) to regulate the expression of the gRNAi in a Dox dependent manner. We show that H1/TO promoters of varying length and a U6/TO promoter can edit DNA with similar efficiency in vitro, in a Dox dependent manner. We also demonstrate that our inducible gRNAi vector can be used to edit the genomes of neurons in vivo within the mouse brain in a Dox dependent manner. Genome editing can be induced in vivo with this system by supplying animals Dox containing food for as little as 1 day. This system might be cross compatible with many existing S. pyogenes Cas9 systems (i.e., Cas9 mouse, CRISPRi, etc.), and therefore it likely can be used to render these systems inducible as well. PMID:27587996

Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis

PubMed Central

Penna, Pete; Meckfessel, Matthew H.; Preston, Norman

2014-01-01

Background Acne vulgaris is a chronic skin disease with a high prevalence. Left untreated or inadequately treated, acne vulgaris can lead to psychological and physical scarring, as well as to unnecessary medical expenses. Oral isotretinoin is an effective treatment for severe resistant nodular and conglobate acne vulgaris. A regimen consisting of a fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO) with oral doxycycline 100 mg (A-BPO/D) has been demonstrated to be efficacious and well tolerated in patients with severe acne and may be an alternative to oral isotretinoin for some patients with severe acne. Objective The objective of this analysis was to compare the relative efficacy and associated costs of A-BPO/D versus oral isotretinoin. Methods In this analysis, comparisons of relative efficacy were made using previously published studies involving similar patient populations with severe acne that warrant the use of oral isotretinoin. The pricing for oral doxycycline and oral isotretinoin was estimated based on the maximum allowable cost from 9 states, and the pricing for A-BPO was calculated as the range between the average wholesale price and the wholesale acquisition cost. For this analysis, 2 treatment models were generated to compare costs: (1) a basic treatment model that examined the costs of an initial regimen of either A-BPO/D or oral isotretinoin without considering probable outcomes, and (2) a long-term model that factored in likely treatment outcomes and subsequent treatments into associated costs. The basic treatment model assumed that patients would be prescribed a single regimen of A-BPO/D for 12 weeks or oral isotretinoin for 20 weeks. The long-term model considered the probability of each treatment successfully managing patients' acne, as well as likely additional regimens of A-BPO monotherapy or an additional regimen of oral isotretinoin. As a result of different treatment durations, the costs for each treatment were

A randomized controlled trial of treatment options for troublesome uterine bleeding in Implanon users

PubMed Central

Weisberg, E.; Hickey, M.; Palmer, D.; O'Connor, V.; Salamonsen, L.A.; Findlay, J.K.; Fraser, I.S.

2009-01-01

BACKGROUND Pilot data have indicated that both doxycycline alone and mifepristone combined with ethinyl estradiol (EE) are effective in stopping episodes of bleeding in Implanon users with troublesome bleeding. We compared four treatments against a placebo in Implanon users and tested whether repeated treatment improved subsequent bleeding patterns. METHOD Implanon users aged 18–45 years were randomized to treatment with (i) mifepristone 25 mg given twice on day 1 followed by 4 days of EE 20 µg; (ii) doxycycline 100 mg twice daily for 5 days; (iii) mifepristone 25 mg given twice on day 1 plus doxycycline 100 mg twice daily for 5 days; (iv) doxycycline 100 mg twice daily with EE 20 µg daily; and (v) placebo twice daily for 5 days. The primary end-point was the number of days of bleeding/spotting immediately following initiation of the first 5-day course of each therapy, compared with placebo. RESULTS There were 204 women assigned to treatment. Mifepristone in combination with either EE or doxycycline was significantly more effective in stopping an episode of bleeding (mean 4.0 days (CI 3.5–4.6) and 4.4 days (CI 3.8–5.2), respectively) than doxycycline alone or in combination with EE, or placebo (6.4 days (CI 4.4–9.2), 6.4 days (CI 4.8–8.6) and 6.4 days (CL 5.1–8.0), respectively). CONCLUSION Mifepristone combined with either EE or doxycycline was significantly more effective than placebo in terminating an episode of bleeding in Implanon users. However there was no improvement in subsequent bleeding patterns. Trial registration number: ACTR # 012605000206628. PMID:19369294

Tetracycline and Pregnancy

MedlinePlus

... to a group of antibiotics that includes minocycline, oxytetracycline, doxycycline. In general, the information in this fact ... other medications in this group such as minocycline, oxytetracycline, or doxycycline instead of tetracycline? Does that still ...

77 FR 12063 - Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Nonprescription Drugs...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-28

... consumer studies needed to assess proper use of a MedKit containing doxycycline to be taken in the event of... doxycycline hyclate. FDA intends to make background material available to the public no later than 2 business...

Metalloproteinase Inhibition Protects against Reductions in Circulating Adrenomedullin during Lead-induced Acute Hypertension.

PubMed

Nascimento, Regina A; Mendes, Gabryella; Possomato-Vieira, Jose S; Gonçalves-Rizzi, Victor Hugo; Kushima, Hélio; Delella, Flavia K; Dias-Junior, Carlos A

2015-06-01

Intoxication with lead (Pb) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP-2) seems to cleave vasoactive peptides. This study examined whether MMP-2 and MMP-9 levels/activities increase after acute intoxication with low lead concentrations and whether these changes were associated with increases in blood pressure and circulating endothelin-1 or with reductions in circulating adrenomedullin and calcitonin gene-related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. Wistar rats received intraperitoneally (i.p.) 1st dose 8 μg/100 g of lead (or sodium) acetate, a subsequent dose of 0.1 μg/100 g to cover daily loss and treatment with doxycycline (30 mg/kg/day) or water by gavage for 7 days. Similar whole-blood lead levels (9 μg/dL) were found in lead-exposed rats treated with either doxycycline or water. Lead-induced increases in systolic blood pressure (from 143 ± 2 to 167 ± 3 mmHg) and gelatin zymography of plasma samples showed that lead increased MMP-9 (but not MMP-2) levels. Both lead-induced increased MMP-9 activity and hypertension were blunted by doxycycline. Doxycycline also prevented lead-induced reductions in circulating adrenomedullin. No significant changes in plasma levels of endothelin-1 or CGRP were found. Lead-induced decreases in nitric oxide markers and antioxidant status were not prevented by doxycycline. In conclusion, acute lead exposure increases blood pressure and MMP-9 activity, which were blunted by doxycycline. These findings suggest that MMP-9 may contribute with lead-induced hypertension by cleaving the vasodilatory peptide adrenomedullin, thereby inhibiting adrenomedullin-dependent lowering of blood pressure. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Combinations of registered drugs reduce treatment times required to deplete Wolbachia in the Litomosoides sigmodontis mouse model

PubMed Central

Specht, Sabine; Arriens, Sandra; Hübner, Marc P.; Klarmann-Schulz, Ute; Koschel, Marianne; Sternberg, Sonja; Martin, Coralie; Taylor, Mark J.; Hoerauf, Achim

2018-01-01

Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4–6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of

Combinations of registered drugs reduce treatment times required to deplete Wolbachia in the Litomosoides sigmodontis mouse model.

PubMed

Specht, Sabine; Pfarr, Kenneth M; Arriens, Sandra; Hübner, Marc P; Klarmann-Schulz, Ute; Koschel, Marianne; Sternberg, Sonja; Martin, Coralie; Ford, Louise; Taylor, Mark J; Hoerauf, Achim

2018-01-01

Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4-6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of no

Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness.

PubMed

Hjoberg, Josephine; Shore, Stephanie; Kobzik, Lester; Okinaga, Shoji; Hallock, Arlene; Vallone, Joseph; Subramaniam, Venkat; De Sanctis, George T; Elias, Jack A; Drazen, Jeffrey M; Silverman, Eric S

2004-07-01

Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from approximately 10 parts per billion to a plateau of approximately 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function.

Antimicrobial susceptibility pattern of Brachyspira intermedia isolates from European layers.

PubMed

Verlinden, Marc; Boyen, Filip; Pasmans, Frank; Garmyn, An; Haesebrouck, Freddy; Martel, An

2011-09-01

A broth microdilution method was used to determine the antimicrobial susceptibility of 20 Brachyspira intermedia isolates obtained from different layer flocks in Belgium and The Netherlands between 2008 and 2010. The antimicrobial agents used were tylosin, tilmicosin, tiamulin, valnemulin, doxycycline, and lincomycin. The minimal inhibitory concentration (MIC) distribution patterns of tylosin, tilmicosin, lincomycin, and doxycycline were bimodal, demonstrating acquired resistance against doxycycline in three strains, against the macrolides in two strains, and against lincomycin in one strain. The MICs of tiamulin and valnemulin showed a monomodal distribution, but with tailing toward the higher MIC values, possibly suggesting low-level acquired resistance in six isolates. Sequencing revealed a G1058C mutation in the 16S rRNA gene in all doxycycline-resistant strains. The strain resistant to tylosin, tilmicosin, and lincomycin had an A2058T mutation in the 23S rRNA gene.

Chemoprevention of Prostate Cancer by Naturally Occurring and Synthetic Organoselenium Compounds

DTIC Science & Technology

2010-12-01

the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC...rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol 2009;9:8-22 36. Wan X, Harkavy B, Shen N, Grohar P

SCI with Brain Injury: Bedside-to-Bench Modeling for Developing Treatment and Rehabilitation Strategies

DTIC Science & Technology

2012-10-01

SIMVASTATIN 2 SIMVASTATIN 1 METOPROLOL 1 METOPROLOL 1 Discharge  Medications Note that the length of stay in rehabilitation is shorter in SCVMC, a...ENOXAPARIN 3 GABAPENTIN 3 GABAPENTIN 2 DOXYCYCLINE 3 DOXYCYCLINE 1 LISINOPRIL 3 LISINOPRIL 1 CHLORHEXIDINE 2 CHLORHEXIDINE 2 METOPROLOL 2 METOPROLOL 2

Doxycycline-Regulated 3T3-L1 Preadipocyte Cell Line with Inducible, Stable Expression of Adenoviral E4orf1 Gene: A Cell Model to Study Insulin-Independent Glucose Disposal

PubMed Central

Krishnapuram, Rashmi; Dhurandhar, Emily J.; Dubuisson, Olga; Hegde, Vijay; Dhurandhar, Nikhil V.

2013-01-01

Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1). Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin. PMID:23544159

Doxycycline-regulated 3T3-L1 preadipocyte cell line with inducible, stable expression of adenoviral E4orf1 gene: a cell model to study insulin-independent glucose disposal.

PubMed

Krishnapuram, Rashmi; Dhurandhar, Emily J; Dubuisson, Olga; Hegde, Vijay; Dhurandhar, Nikhil V

2013-01-01

Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1). Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin.

Synthesis and anti Methicillin resistant Staphylococcus aureus activity of substituted chalcones alone and in combination with non-beta-lactam antibiotics.

PubMed

Tran, Thanh-Dao; Do, Tuong-Ha; Tran, Ngoc-Chau; Ngo, Trieu-Du; Huynh, Thi-Ngoc-Phuong; Tran, Cat-Dong; Thai, Khac-Minh

2012-07-15

A total of 30 chalcone analogues was synthesized via a base catalyzed Claisen Schmidt condensation and screened for their in vitro antibacterial activity against Methicillin-sensitive Staphylococcus aureus (MSSA) and Methicillin-resistant Staphylococcus aureus (MRSA) alone or in combination with non beta-lactam antibiotics namely ciprofloxacin, chloramphenicol, erythromycin, vancomycin, doxycycline and gentamicin. In the checkerboard technique, fractional inhibitory concentration indices (FICI) show that the following combinations like ciprofloxacin with 25 (4'-bromo-2-hydroxychalcone); doxycycline with 21 (4-hydroxychalcone); doxycycline with 25; and doxycycline with 4 (2',2-dihydroxychalcone) were synergistic against MRSA. In term SAR study, the relationship between chalcone structure and their antibacterial activity against S. aureus and synergy with tested antibiotics were discussed. Possible mechanisms for antibacterial activity of chalcones alone as well as the synergistic effect in combinations were proposed by molecular modeling studies, respectively. Combinations of chalcones with conventional antibiotics could be an effective alternative in the treatment of infection caused by MRSA. Copyright © 2012 Elsevier Ltd. All rights reserved.

Influence of Market Competition on Tetracycline Pricing and Impact of Price Increases on Clinician Prescribing Behavior.

PubMed

Barbieri, John S; Margolis, David J; Brod, Bruce A

2017-12-01

Oral tetracyclines are commonly used for acne and other conditions. Recent generic price increases threaten access to these medications. Using the OptumInsight Clinformatics DataMart, we retrospectively evaluated the underlying factors behind these price increases for oral tetracylines using the framework of a competitive market and evaluated the impact of these price increases on prescribing practices. Between 2011 and 2013, the mean cost of doxycycline hyclate prescriptions increased from $7.16 to $139.89 and the mean out-of-pocket cost increased by $9.69. A comparable cost increase was not observed for doxycycline monohydrate or minocycline. There was no significant association between the cost of doxycycline hyclate and market concentration as assessed by the Herfindahl-Hirschman index (β = 0.030, 95% confidence interval -0.019 to 0.079, P = 0.213) and the market was highly concentrated throughout the study period. The percentage of prescriptions for doxycycline hyclate decreased by 1.9% from 2011 to 2013. This dramatic increase in the cost of doxycycline hyclate is not easily explained using the framework of a competitive market, suggesting that noncompetitive market forces may be responsible. In addition, clinicians have not altered their prescribing behavior in response to this price increase, suggesting that clinician or pharmacy level interventions could potentially increase the use of less costly substitutes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Self-Reported Treatment Practices by Healthcare Providers Could Lead to Death from Rocky Mountain Spotted Fever

PubMed Central

Zientek, Jillian; Dahlgren, F. Scott; McQuiston, Jennifer H.; Regan, Joanna

2015-01-01

Among 2012 Docstyle survey respondents, 80% identified doxycycline as the appropriate treatment for Rocky Mountain spotted fever in patients ≥8 years old, but only 35% correctly chose doxycycline in patients <8 years old. These findings raise concerns about the higher pediatric case-fatality rate of Rocky Mountain spotted fever observed nationally. Targeted education efforts are needed. PMID:24252781

Time-controllable Nkcc1 knockdown replicates reversible hearing loss in postnatal mice.

PubMed

Watabe, Takahisa; Xu, Ming; Watanabe, Miho; Nabekura, Junichi; Higuchi, Taiga; Hori, Karin; Sato, Mitsuo P; Nin, Fumiaki; Hibino, Hiroshi; Ogawa, Kaoru; Masuda, Masatsugu; Tanaka, Kenji F

2017-10-19

Identification of the causal effects of specific proteins on recurrent and partially reversible hearing loss has been difficult because of the lack of an animal model that provides reversible gene knockdown. We have developed the transgenic mouse line Actin-tTS::Nkcc1 tetO/tetO for manipulatable expression of the cochlear K + circulation protein, NKCC1. Nkcc1 transcription was blocked by the binding of a tetracycline-dependent transcriptional silencer to the tetracycline operator sequences inserted upstream of the Nkcc1 translation initiation site. Administration of the tetracycline derivative doxycycline reversibly regulated Nkcc1 knockdown. Progeny from pregnant/lactating mothers fed doxycycline-free chow from embryonic day 0 showed strong suppression of Nkcc1 expression (~90% downregulation) and Nkcc1 null phenotypes at postnatal day 35 (P35). P35 transgenic mice from mothers fed doxycycline-free chow starting at P0 (delivery) showed weaker suppression of Nkcc1 expression (~70% downregulation) and less hearing loss with mild cochlear structural changes. Treatment of these mice at P35 with doxycycline for 2 weeks reactivated Nkcc1 transcription to control levels and improved hearing level at high frequency; i.e., these doxycycline-treated mice exhibited partially reversible hearing loss. Thus, development of the Actin-tTS::Nkcc1 tetO/tetO transgenic mouse line provides a mouse model for the study of variable hearing loss through reversible knockdown of Nkcc1.

Fabrication of magnetite nano particles and modification with metal organic framework of Zn(2+) for sorption of doxycyline.

PubMed

Ghassemi Nooreini, Mahsa; Ahmad Panahi, Homayon

2016-10-15

This study presents a novel method for synthesis and characterization of a metal-organic framework and application in drug delivery. The first step was synthesis of amino functionalized magnetite that was then modified by a metal-organic framework of Zn(2+). This newly developed nano-sorbent was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive x-ray spectroscopy, thermogravimetric analysis, vibrating sample magnetometer and x-ray diffraction. Doxycycline was loaded to the nano-sorbent and effects of the variable parameters, kinetics of adsorption, release and capacity of adsorption were investigated. Test results specified maximum sorption of 21.5mgg(-1) for doxycycline in conditions of nano-sorbent at pH 7 and optimum time of 10min. Equilibrium adsorption data were analyzed by the Langmuir, Freundlich and Temkin models. Results showed that about 40% of doxycycline was released in simulated gastric fluid for the 30min and more than 70% was released in simulated intestinal fluid during 12h. These results were satisfactory and demonstrate that this new nano-sorbent modified with metal-organic framework had a good level of efficiency for drug delivery of doxycycline. Copyright © 2016 Elsevier B.V. All rights reserved.

Risk Factors for Fatal Outcome From Rocky Mountain Spotted Fever in a Highly Endemic Area—Arizona, 2002–2011

PubMed Central

Regan, Joanna J.; Traeger, Marc S.; Humpherys, Dwight; Mahoney, Dianna L.; Martinez, Michelle; Emerson, Ginny L.; Tack, Danielle M.; Geissler, Aimee; Yasmin, Seema; Lawson, Regina; Williams, Velda; Hamilton, Charlene; Levy, Craig; Komatsu, Ken; Yost, David A.; McQuiston, Jennifer H.

2016-01-01

Background Rocky Mountain spotted fever (RMSF) is a disease that now causes significant morbidity and mortality on several American Indian reservations in Arizona. Although the disease is treatable, reported RMSF case fatality rates from this region are high (7%) compared to the rest of the nation (<1%), suggesting a need to identify clinical points for intervention. Methods The first 205 cases from this region were reviewed and fatal RMSF cases were compared to nonfatal cases to determine clinical risk factors for fatal outcome. Results Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3), although both groups of case patients presented for care early (median, day 2). Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea, history of alcoholism or chronic lung disease, and abnormal laboratory results such as elevated liver aminotransferases. Rash, history of tick bite, thrombocytopenia, and hyponatremia were often absent at initial presentation. Conclusions Earlier treatment with doxycycline can decrease morbidity and mortality from RMSF in this region. Recognition of risk factors associated with doxycycline delay and fatal outcome, such as early gastrointestinal symptoms and a history of alcoholism or chronic lung disease, may be useful in guiding early treatment decisions. Healthcare providers should have a low threshold for initiating doxycycline whenever treating febrile or potentially septic patients from tribal lands in Arizona, even if an alternative diagnosis seems more likely and classic findings of RMSF are absent. PMID:25697742

Matrix Metalloproteinase-2 Activity is Associated with Divergent Regulation of Calponin-1 in Conductance and Resistance Arteries in Hypertension-induced Early Vascular Dysfunction and Remodelling.

PubMed

Parente, Juliana M; Pereira, Camila A; Oliveira-Paula, Gustavo H; Tanus-Santos, José E; Tostes, Rita C; Castro, Michele M

2017-10-01

Matrix metalloproteinase (MMP)-2 participates in hypertension-induced maladaptive vascular remodelling by degrading extra- and intracellular proteins. The consequent extracellular matrix rearrangement and phenotype switch of vascular smooth muscle cells (VSMCs) lead to increased cellular migration and proliferation. As calponin-1 degradation by MMP-2 may lead to VSMC proliferation during hypertension, the hypothesis of this study is that increased MMP-2 activity contributes to early hypertension-induced maladaptive remodelling in conductance and resistance arteries via regulation of calponin-1. The main objective was to analyse whether MMP-2 exerts similar effects on the structure and function of the resistance and conductance arteries during early hypertension. Two-kidney, one-clip (2K-1C) hypertensive male rats and corresponding controls were treated with doxycycline (30 mg/kg/day) or water until reaching one week of hypertension. Systolic blood pressure was increased in 2K-1C rats, and doxycycline did not reduce it. Aortas and mesenteric arteries were analysed. MMP-2 activity and expression were increased in both arteries, and doxycycline reduced it. Significant hypertrophic remodelling and VSMC proliferation were observed in aortas but not in mesenteric arteries of 2K-1C rats. The contractility of mesenteric arteries to phenylephrine was increased in 2K-1C rats, and doxycycline prevented this alteration. The potency of phenylephrine to contract aortas of 2K-1C rats was increased, and doxycycline decreased it. Whereas calponin-1 expression was increased in 2K-1C mesenteric arteries, calponin-1 was reduced in aortas. Doxycycline treatment reverted changes in calponin-1 expression. MMP-2 contributes to hypertrophic remodelling in aortas by decreasing calponin-1 levels, which may result in VSMC proliferation. On the other hand, MMP-2-dependent increased calponin-1 in mesenteric arteries may contribute to vascular hypercontractility in 2K-1C rats. Divergent

Self-reported treatment practices by healthcare providers could lead to death from Rocky Mountain spotted fever.

PubMed

Zientek, Jillian; Dahlgren, F Scott; McQuiston, Jennifer H; Regan, Joanna

2014-02-01

Among 2012 Docstyle survey respondents, 80% identified doxycycline as the appropriate treatment for Rocky Mountain spotted fever in patients ≥ 8 years old, but only 35% correctly chose doxycycline in patients <8 years old. These findings raise concerns about the higher pediatric case-fatality rate of Rocky Mountain spotted fever observed nationally. Targeted education efforts are needed. Crown Copyright © 2014. Published by Mosby, Inc. All rights reserved.

Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011.

PubMed

Regan, Joanna J; Traeger, Marc S; Humpherys, Dwight; Mahoney, Dianna L; Martinez, Michelle; Emerson, Ginny L; Tack, Danielle M; Geissler, Aimee; Yasmin, Seema; Lawson, Regina; Williams, Velda; Hamilton, Charlene; Levy, Craig; Komatsu, Ken; Yost, David A; McQuiston, Jennifer H

2015-06-01

Rocky Mountain spotted fever (RMSF) is a disease that now causes significant morbidity and mortality on several American Indian reservations in Arizona. Although the disease is treatable, reported RMSF case fatality rates from this region are high (7%) compared to the rest of the nation (<1%), suggesting a need to identify clinical points for intervention. The first 205 cases from this region were reviewed and fatal RMSF cases were compared to nonfatal cases to determine clinical risk factors for fatal outcome. Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3), although both groups of case patients presented for care early (median, day 2). Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea, history of alcoholism or chronic lung disease, and abnormal laboratory results such as elevated liver aminotransferases. Rash, history of tick bite, thrombocytopenia, and hyponatremia were often absent at initial presentation. Earlier treatment with doxycycline can decrease morbidity and mortality from RMSF in this region. Recognition of risk factors associated with doxycycline delay and fatal outcome, such as early gastrointestinal symptoms and a history of alcoholism or chronic lung disease, may be useful in guiding early treatment decisions. Healthcare providers should have a low threshold for initiating doxycycline whenever treating febrile or potentially septic patients from tribal lands in Arizona, even if an alternative diagnosis seems more likely and classic findings of RMSF are absent. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

ATNT: an enhanced system for expression of polycistronic secondary metabolite gene clusters in Aspergillus niger.

PubMed

Geib, Elena; Brock, Matthias

2017-01-01

Fungi are treasure chests for yet unexplored natural products. However, exploitation of their real potential remains difficult as a significant proportion of biosynthetic gene clusters appears silent under standard laboratory conditions. Therefore, elucidation of novel products requires gene activation or heterologous expression. For heterologous gene expression, we previously developed an expression platform in Aspergillus niger that is based on the transcriptional regulator TerR and its target promoter P terA . In this study, we extended this system by regulating expression of terR  by the doxycycline inducible Tet-on system. Reporter genes cloned under the control of the target promoter P terA remained silent in the absence of doxycycline, but were strongly expressed when doxycycline was added. Reporter quantification revealed that the coupled system results in about five times higher expression rates compared to gene expression under direct control of the Tet-on system. As production of secondary metabolites generally requires the expression of several biosynthetic genes, the suitability of the self-cleaving viral peptide sequence P2A was tested in this optimised expression system. P2A allowed polycistronic expression of genes required for Asp-melanin formation in combination with the gene coding for the red fluorescent protein tdTomato. Gene expression and Asp-melanin formation was prevented in the absence of doxycycline and strongly induced by addition of doxycycline. Fluorescence studies confirmed the correct subcellular localisation of the respective enzymes. This tightly regulated but strongly inducible expression system enables high level production of secondary metabolites most likely even those with toxic potential. Furthermore, this system is compatible with polycistronic gene expression and, thus, suitable for the discovery of novel natural products.

Tularemia type A in captive Bornean orangutans (Pongo pygmaeus pygmaeus).

PubMed

Ketz-Riley, Cornelia J; Kennedy, George A; Carpenter, James W; Zeidner, Nordin S; Petersen, Jeannine M

2009-06-01

In 2003, tularemia was suspected to be the cause of severe illness in two orangutans (Pongo pygmaeus pygmaeus) and the cause of death in a third orangutan at an urban zoo. The two sick orangutans were treated two times under chemical immobilization with i.v. doxycycline, fluids, and antipyretic drugs, followed by a sustained course of oral doxycycline. The rest of the orangutan group was treated prophylactically with oral doxycycline. Postmortem diagnosis was obtained via immunohistochemistry and bacterial culture that revealed Francisella tularensis type A. Tularemia was also confirmed in the two surviving orangutans via paired serology testing. In addition, F. tularensis was identified in two wild rabbit carcasses submitted during a die-off, several weeks prior to the tularemia outbreak in the apes, indicating that rabbits were possibly a reservoir for tularemia within the zoo premises.

SCI with Brain Injury: Bedside-to-Bench Modeling for Developing Treatment and Rehabilitation Strategies

DTIC Science & Technology

2012-10-01

GLUCONATE 1 SIMVASTATIN 2 SIMVASTATIN 1 METOPROLOL 1 METOPROLOL 1 Discharge  Medications Note that the length of stay in rehabilitation is shorter in SCVMC...ENOXAPARIN 3 ENOXAPARIN 3 GABAPENTIN 3 GABAPENTIN 2 DOXYCYCLINE 3 DOXYCYCLINE 1 LISINOPRIL 3 LISINOPRIL 1 CHLORHEXIDINE 2 CHLORHEXIDINE 2 METOPROLOL 2... METOPROLOL 2 DEXTROSE 2 DEXTROSE 1 MICONAZOLE 2 MICONAZOLE 1 HEPARIN 1 HEPARIN 3 FENTANYL 1 FENTANYL 2 BACLOFEN 1 BACLOFEN 1 FERROUS  SULFATE 1 FERROUS

Frequency and Genetic Determinants of Tigecycline Resistance in Clinically Isolated Stenotrophomonas maltophilia in Beijing, China.

PubMed

Zhao, Jin; Liu, Yunxi; Liu, Yi; Wang, Dong; Ni, Wentao; Wang, Rui; Liu, Youning; Zhang, Bo

2018-01-01

Stenotrophomonas maltophilia is an emerging nosocomial pathogen with high resistance to most clinically used antimicrobials. Tigecycline is a potential alternative antimicrobial for S. maltophilia infection treatment, but its resistance mechanism in clinical isolates is not fully elucidated. We investigated the antimicrobial susceptibility of 450 S. maltophilia isolated during 2012-2015 from three university hospitals in Beijing, China. These strains exhibited high susceptibility to minocycline (98.44%), sulfamethoxazole/trimethoprim (87.56%), tigecycline (77.78 %), doxycycline (81.33%), levofloxacin (67.56%), and ticarcillin/clavulanate (73.00%). The susceptibility of tigecycline-nonsusceptible strains (TNS) to doxycycline and levofloxacin was much lower than that of tigecycline-susceptible strains (TSS) (25.00% vs. 97.71% for doxycycline, P < 0.001; 17.00% vs. 82.00% for levofloxacin, P < 0.001). We further selected 48 TNS and TSS and compared the detection rate of eight tetracycline-specific genes by PCR and the expression level of six intrinsic multidrug resistance efflux pumps by real-time PCR. Only one tetB and two tetH genes in TNS and three tetH genes in TSS were detected, and the detection rate had no difference. The average expression level of smeD in TNS was higher than that in TSS [20.59 (11.53, 112.54) vs. 2.07 (0.80, 4.96), P < 0.001], while the average expression levels of smeA , smeI , smeO , smeV , and smrA were not significantly different, indicating that smeDEF was the predominant resistance genetic determinant in clinical S. maltophilia . Higher smeD expression was also observed in levofloxacin- and doxycycline-nonsusceptible isolates than in their corresponding susceptible isolates [16.46 (5.83, 102.24) vs. 2.72 (0.80, 6.25) for doxycycline, P < 0.001; 19.69 (8.07, 115.10) vs. 3.01(1.00, 6.03), P < 0.001], indicating that smeDEF was also the resistance genetic determinant to levofloxacin and doxycycline. The consistent resistance profile and

Removal of veterinary antibiotics from wastewater by electrocoagulation.

PubMed

Baran, Wojciech; Adamek, Ewa; Jajko, Marcin; Sobczak, Andrzej

2018-03-01

The aim of this study was to assess the effectiveness of veterinary antibiotic removal from wastewater using an electrocoagulation method. The removal efficiency of ampicillin, doxycycline, sulfathiazole and tylosin; the antibiotic degradation degree after electrolysis; and the toxicity and qualitative composition of antibiotic solutions after electrocoagulation were determined in the experiments. HPLC-QTOF was used for quantitative and qualitative determination. The eco-toxicity was assessed using the MARA ® assay. After electrocoagulation, the concentration of ampicillin, doxycycline, sulfathiazole and tylosin in wastewater decreased 3.6 ± 3.2%, ∼100%, 3.3 ± 0.4% and 3.1 ± 0.3%, respectively. Doxycycline was the only antibiotic effectively removed from wastewater during electrocoagulation. Simultaneously, part of this antibiotic underwent oxidative degradation. As a result of this process, the eco-toxicity in the reaction environment decreased. Copyright © 2017. Published by Elsevier Ltd.

Outcomes of resistance-guided sequential treatment of Mycoplasma genitalium infections: a prospective evaluation.

PubMed

Read, T R H; Fairley, C K; Murray, G L; Jensen, J S; Danielewski, J; Worthington, K; Doyle, M; Mokany, E; Tan, L; Chow, E P F; Garland, S M; Bradshaw, C S

2018-06-05

Rising macrolide and quinolone resistance in Mycoplasma genitalium necessitate new treatment approaches. We evaluated outcomes of sequential antimicrobial therapy for M.genitalium guided by a macrolide-resistance assay. In mid-2016 Melbourne Sexual Health Centre switched from azithromycin to doxycycline (100mg twice daily,7 days) for non-gonococcal urethritis/cervicitis/proctitis. Cases were tested for M. genitalium and macrolide-resistance mutations (MRM) by polymerase chain reaction (PCR). Directly after doxycycline, MRM-negative infections received 2.5g azithromycin (1g then 500mg daily for 3 days), and MRM-positive infections received sitafloxacin (100mg twice daily, 7 days). Assessment of test-of-cure and reinfection risk, occurred 14-90 days after the second antibiotic. Those reporting condomless sex with incompletely treated partners were excluded. Of 244 evaluable M. genitalium infections (52 women, 68 heterosexual men, 124 men who have sex with men) diagnosed from 20 June 2016 to 15 May 2017, MRM were detected in 167 [68.4% (95%confidence interval(CI):62.2%, 74.2%)]. Treatment with doxycycline decreased bacterial load by a mean 2.60 log10 (n=56, p<0.0001). Microbiologic cure occurred in: 73/77 MRM-negative infections [94.8% (95%CI:87.2%, 98.6%)] and in 154/167 MRM-positive infections [92.2% (95%CI:87.1%, 95.8%)]. Selection of macrolide-resistance occurred in only 2 [2.6% (95%CI: 0.3%, 9.2%)] of 76 macrolide-susceptible infections. Proportions reporting no missed doses and no adverse events, respectively, were: doxycycline 89.9% and 86.6%, sitafloxacin 90.8% and 80.5%, azithromycin 100% and 91.4%. In the context of high levels of antimicrobial resistance, switching from azithromycin to doxycycline for presumptive treatment of M. genitalium, followed by resistance-guided therapy, cured ≥92% of infections, with infrequent selection of macrolide resistance.

In vivo screening of five phytochemicals/extracts and a fungal immunomodulatory protein against colibacillosis in broilers.

PubMed

Peek, H W; Halkes, S B A; Tomassen, M M M; Mes, J J; Landman, W J M

2013-01-01

Five phytochemicals/extracts (an extract from Echinacea purpurea, a β-glucan-rich extract from Shiitake, betaine [Betain™], curcumin from Curcuma longa [turmeric] powder, carvacrol and also a recombinant fungal immunomodulatory protein [FIP] from Ganoderma lucidum) cloned and expressed in Escherichia coli were investigated for their anticolibacillosis potential in three chicken experiments, which were conducted in floor pens. Birds that were inoculated with E. coli intratracheally were treated with the phytochemicals/extracts or the FIP and compared with doxycycline-medicated and non-medicated infected broilers. Non-medicated and non-infected birds were used as negative controls. Mortality, colibacillosis lesions and body weight gains were used as parameters. Considering the sum of dead birds and chickens with generalized colibacillosis per group, there was no significant difference between the positive control groups and birds treated with phytochemicals/extracts or the FIP. In contrast, doxycycline-treated birds showed significantly lower mortality and generalized colibacillosis. Moreover, none of the phytochemicals/extracts and the FIP improved recovery from colibacillosis lesions, while all doxycycline-treated broilers recovered completely. The negative control birds and doxycycline-treated groups consistently showed the highest weight gains. Pulsed-field gel electrophoresis of reisolates showed that they were genetically indistinguishable from the inoculation strain. In conclusion, none of the tested phytochemicals/extracts and the FIP significantly reduced the E. coli-induced mortality and generalized colibacillosis, and nor did they improve recovery from colibacillosis lesions.

[Lymphogranuloma venereum proctocolitis in men with HIV-1 infection].

PubMed

Heras, Eva; Llibre, Josep M; Martró, Elisa; Casabona, Jordi; Martin-Iguacel, Raquel; Martín, Raquel; Sirera, Guillem

2011-02-01

We present a series of 15 cases with lymphogranuloma venereum (LGV) with the aim of evaluating the response to a 21-day oral course of doxycycline (100mg twice daily). It is an observational study where we describe a series of cases with LGV diagnosed in the Hospital Germans Trias i Pujol's HIV Unit between March 2008 and April 2009. All our patients were HIV infected men who had sex with men with proctitis in 80% of the cases. In all of them Chlamydia trachomatis was determined by PCR on rectal swab specimens, with a negative result after 21 days of treatment with doxycycline. Serovar L2 was confirmed in all the specimens with the reverse hybridization technique. A high index of clinical suspicion is the mainstay to the early diagnosis of LGV since the clinical presentation remains unspecific. The treatment with doxycycline eradicates C. trachomatis in HIV patients with LGV. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Propionibacterium acnes is developing gradual increase in resistance to oral tetracyclines.

PubMed

Nakase, Keisuke; Nakaminami, Hidemasa; Takenaka, Yuko; Hayashi, Nobukazu; Kawashima, Makoto; Noguchi, Norihisa

2017-01-01

Propionibacterium acnes is an anaerobic bacterium that causes deep infection in organs and prosthetic joints, in addition to acne vulgaris. Many tetracycline-resistant P. acnes strains have been isolated because oral tetracyclines are frequently used as an acne treatment against P. acnes. In this study, we found a novel tetracycline resistance mechanism in P. acnes. Three doxycycline-resistant (MIC: 16 µg ml-1) strains were isolated from 69 strains in acne patients in Japan between 2010 and 2011. Additionally, six insusceptible strains (MIC: 1-2 µg ml-1) that had reduced susceptibility compared to susceptible strains (MIC: ≤0.5 µg ml-1) were identified. All doxycycline-resistant strains had a G1036C mutation in the 16S rRNA gene in addition to an amino acid substitution in the ribosomal S10 protein encoded by rpsJ. By contrast, insusceptible strains had an amino acid substitution in the S10 protein but no mutation in the 16S rRNA. When the mutant with decreased susceptibility to doxycycline was obtained in vitro, only the mutated S10 protein was found (MIC: 4 µg ml-1), not the mutated 16S rRNA gene. This result shows that the S10 protein amino acid substitution contributes to reduced doxycycline susceptibility in P. acnes and suggests that tetracycline resistance is acquired through a 16S rRNA mutation after the S10 protein amino acid substitution causes reduced susceptibility.

The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific.

PubMed

Elmes, N J; Nasveld, P E; Kitchener, S J; Kocisko, D A; Edstein, M D

2008-11-01

Tafenoquine is being developed for radical cure and post-exposure prophylaxis of Plasmodium vivax malaria. In an open-label study, 1512 Australian Defence Force personnel received one of three tafenoquine 3 d regimens [400 mg once daily (od), 200 mg twice daily (bid), 200 mg od] or daily primaquine (22.5 mg) plus doxycycline (100 mg) over 14 d in Bougainville and in Timor-Leste for post-exposure prophylaxis. The relapse rate of subjects treated in Bougainville with tafenoquine (n=173) was 1.2% (200 mg bid x 3 d) and 2.3% (400 mg od x 3 d), while primaquine plus doxycycline (n=175) was 3.4%. For subjects treated in Timor-Leste with tafenoquine (n=636), the relapse rate was 4.9% (200 mg od x 3 d), 5.3% (200 mg bid x 3 d) and 11.0% (400 mg od x 3d), while primaquine plus doxycycline (n=289) was 10.0%. The most frequent adverse events reported across all groups were nausea, abdominal distress and diarrhoea. There was a dose-dependent reduction in adverse events with a reduced dose of tafenoquine, with the lowest dose (total 600 mg over 3 d) producing rates of adverse events equivalent to that of primaquine plus doxycycline. The much shorter dosing regimen of tafenoquine should increase compliance, which is often suboptimal with primaquine after leaving an endemic area. [Australian New Zealand Clinical Trials Registry Number 12607000588493].

In vitro antibiotic susceptibility of Dutch Mycoplasma synoviae field isolates originating from joint lesions and the respiratory tract of commercial poultry.

PubMed

Landman, W J M; Mevius, D J; Veldman, K T; Feberwee, A

2008-08-01

The in vitro susceptibility of 17 Dutch Mycoplasma synoviae isolates from commercial poultry to enrofloxacin, difloxacin, doxycycline, tylosin and tilmicosin was examined. Three isolates originated from joint lesions and 14 were from the respiratory tract. The type strain M. synoviae WVU 1853 was included as a control strain. Antibiotic susceptibility was tested quantitatively using the broth microdilution test. Based on initial and final minimum inhibitory concentration values, all tested isolates were susceptible to doxycycline, tylosin and tilmicosin. Two isolates from the respiratory tract were resistant to enrofloxacin and showed intermediate resistance to difloxacin.

ING4 Loss in Prostate Cancer Progression

DTIC Science & Technology

2015-10-01

determine how loss of ING4 in patients relates to tumor progression. We found the following: 1) Notch3 is a target of Myc required for differentiation. 2...hour doxycycline-treated MKK6 cells. Figure 1: Notch3 induction requires Myc. A. MKK6 was induced in PrECs with a 4 hour doxycycline (Dox) pulse...Levels of MKK6, p38α, active p38α (p-p38α), Myc, Notch3 (full length (FL) or cleaved (TM), and GAPDH over time (hours (h)) measured by

Adverse Events Associated with Prolonged Antibiotic Use

PubMed Central

Meropol, Sharon B.; Chan, K. Arnold; Chen, Zhen; Finkelstein, Jonathan A.; Hennessy, Sean; Lautenbach, Ebbing; Platt, Richard; Schech, Stephanie D.; Shatin, Deborah; Metlay, Joshua P.

2014-01-01

Purpose The Infectious Diseases Society of America and US CDC recommend 60 days of ciprofloxacin, doxycycline or amoxicillin for anthrax prophylaxis. It is not possible to determine severe adverse drug event (ADE) risks from the few people thus far exposed to anthrax prophylaxis. This study’s objective was to estimate risks of severe ADEs associated with long-term ciprofloxacin, doxycycline and amoxicillin exposure using 3 large databases: one electronic medical record (General Practice Research Database) and two claims databases (UnitedHealthcare, HMO Research Network). Methods We include office visit, hospital admission and prescription data for 1/1/1999–6/30/2001. Exposure variable was oral antibiotic person-days (pds). Primary outcome was hospitalization during exposure with ADE diagnoses: anaphylaxis, phototoxicity, hepatotoxicity, nephrotoxicity, seizures, ventricular arrhythmia or infectious colitis. Results We randomly sampled 999,773, 1,047,496 and 1,819,004 patients from Databases A, B and C respectively. 33,183 amoxicillin, 15,250 ciprofloxacin and 50,171 doxycycline prescriptions continued ≥30 days. ADE hospitalizations during long-term exposure were not observed in Database A. ADEs during long-term amoxicillin were seen only in Database C with 5 ADEs or 1.2(0.4–2.7) ADEs/100,000 pds exposure. Long-term ciprofloxacin showed 3 and 4 ADEs with 5.7(1.2–16.6) and 3.5(1.0–9.0) ADEs/100,000 pds in Databases B and C, respectively. Only Database B had ADEs during long-term doxycycline with 3 ADEs or 0.9(0.2–2.6) ADEs/100,000 pds. For most events, the incidence rate ratio, comparing >28 vs.1–28 pds exposure was <1, showing limited evidence for cumulative dose-related ADEs from long-term exposure. Conclusions Long-term amoxicillin, ciprofloxacin and doxycycline appears safe, supporting use of these medications if needed for large-scale post-exposure anthrax prophylaxis. PMID:18215001

Anti-Brucella activity of Caryopteris mongolica Bunge root extract against Brucella melitensis infection in mice.

PubMed

N, Tsevelmaa; B, Narangerel; O, Odgerel; D, Dariimaa; J, Batkhuu

2018-05-03

The current treatment for human brucellosis requires a combination of antibiotics for long periods of time, and the reported incidence and prevalence of the disease vary widely in nomadic livestock of Mongolia. The objective of the present study was to evaluate the in vivo antibacterial activity of the C. mongolica root extract against B. melitensis. In this study, we used of 6 groups of mice (n = 5). Five groups of BALB/c mice were inoculated intraperitoneally with the M16 strain of B. melintensis, as follows: (i) one group was used for pretreatment monitoring; (ii) the control group was administered 2% Tween 80 and was used as the non-treatment group; and the other three groups were treated with one oral gavage per day for 21 days with (iii) doxycycline (2 mg/day), (iv) doxycycline (1 mg/day) with root extract (20 mg/day), and (v) C. mongolica root extract (20 mg/day). The one group that was kept non-infected was used as a healthy control group. This study demonstrated that daily treatment with doxycycline alone and in combination with C. mongolica root extract significantly reduced splenic infection at the end of treatment. However, the spleen index of both the doxycycline-treated and the combination-treated groups of mice decreased by approximately 50% compared to that of the healthy control mouse group. Treatment with the C. mongolica root extract resulted in a 1.47log reduction in splenic infection compared to the non-treatment group, and the spleen index of the C. mongolica-treated group of mice was the same as that of the normal mouse group. In all treatment groups, neutrophil phagocytic activity significantly decreased, and all treatment groups demonstrated splenic regeneration. The present study showed that the C. mongolica root extract may be useful in the treatment of brucellosis patients, in combination with doxycycline or other antibiotics, to reduce the toxicity of high-dosage antibiotics, to prevent the development of antibiotic resistance

Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review.

PubMed

Sanchez, Edgar; Vannier, Edouard; Wormser, Gary P; Hu, Linden T

2016-04-26

Lyme disease, human granulocytic anaplasmosis (HGA), and babesiosis are emerging tick-borne infections. To provide an update on diagnosis, treatment, and prevention of tick-borne infections. Search of PubMed and Scopus for articles on diagnosis, treatment, and prevention of tick-borne infections published in English from January 2005 through December 2015. The search yielded 3550 articles for diagnosis and treatment and 752 articles for prevention. Of these articles, 361 were reviewed in depth. Evidence supports the use of US Food and Drug Administration-approved serologic tests, such as an enzyme immunoassay (EIA), followed by Western blot testing, to diagnose extracutaneous manifestations of Lyme disease. Microscopy and polymerase chain reaction assay of blood specimens are used to diagnose active HGA and babesiosis. The efficacy of oral doxycycline, amoxicillin, and cefuroxime axetil for treating Lyme disease has been established in multiple trials. Ceftriaxone is recommended when parenteral antibiotic therapy is recommended. Multiple trials have shown efficacy for a 10-day course of oral doxycycline for treatment of erythema migrans and for a 14-day course for treatment of early neurologic Lyme disease in ambulatory patients. Evidence indicates that a 10-day course of oral doxycycline is effective for HGA and that a 7- to 10-day course of azithromycin plus atovaquone is effective for mild babesiosis. Based on multiple case reports, a 7- to 10-day course of clindamycin plus quinine is often used to treat severe babesiosis. A recent study supports a minimum of 6 weeks of antibiotics for highly immunocompromised patients with babesiosis, with no parasites detected on blood smear for at least the final 2 weeks of treatment. Evidence is evolving regarding the diagnosis, treatment, and prevention of Lyme disease, HGA, and babesiosis. Recent evidence supports treating patients with erythema migrans for no longer than 10 days when doxycycline is used and prescription

Medical knowledge related to Rocky Mountain spotted fever in Sonora, Mexico.

PubMed

Alvarez-Hernandez, Gerardo; Ernst, Kacey; Acuña-Melendrez, Natalia Haydee; Vargas-Ortega, Anabel Patricia; Candia-Plata, Maria Del Carmen

2018-03-01

Rocky Mountain spotted fever (RMSF) is a tick-borne disease with a high case-fatality rate unless diagnosed promptly and treated timely with doxycycline. Physician knowledge about presentation and treatment can improve outcomes of RMSF in endemic regions, such as Sonora in northern Mexico, where RMSF has caused 1348 non-fatal cases and 247 deaths from 2003 to 2016. A cross-sectional study was conducted with 343 physicians working in medical facilities in Sonora, Mexico. A 25-item questionnaire explored physician knowledge of clinical, epidemiological and preventive aspects of RMSF. Only 62% of physicians agreed that doxycycline should be used as the first choice treatment for children under 8 years with suspected RMSF. Additionally, 40% of primary care physicians correctly identified the time to initiate doxycycline, and 32% correctly identified the case-fatality rate of untreated RMSF in all patients. Inadequate medical knowledge may adversely affect how patients infected with Rickettsia rickettsii are diagnosed and treated. Educational programs that improve the risk perception and medical knowledge about RMSF should be targeted at physicians most likely to have initial contact with diseased patients.

A design of experiment approach for efficient multi-parametric drug testing using a Caenorhabditis elegans model.

PubMed

Letizia, M C; Cornaglia, M; Tranchida, G; Trouillon, R; Gijs, M A M

2018-01-22

When studying the drug effectiveness towards a target model, one should distinguish the effects of the drug itself and of all the other factors that could influence the screening outcome. This comprehensive knowledge is crucial, especially when model organisms are used to study the drug effect at a systemic level, as a higher number of factors can influence the drug-testing outcome. Covering the entire experimental domain and studying the effect of the simultaneous change in several factors would require numerous experiments, which are costly and time-consuming. Therefore, a design of experiment (DoE) approach in drug-testing is emerging as a robust and efficient method to reduce the use of resources, while maximizing the knowledge of the process. Here, we used a 3-factor-Doehlert DoE to characterize the concentration-dependent effect of the drug doxycycline on the development duration of the nematode Caenorhabditis elegans. To cover the experimental space, 13 experiments were designed and performed, where different doxycycline concentrations were tested, while also varying the temperature and the food amount, which are known to influence the duration of C. elegans development. A microfluidic platform was designed to isolate and culture C. elegans larvae, while testing the doxycycline effect with full control of temperature and feeding over the entire development. Our approach allowed predicting the doxycycline effect on C. elegans development in the complete drug concentration/temperature/feeding experimental space, maximizing the understanding of the effect of this antibiotic on the C. elegans development and paving the way towards a standardized and optimized drug-testing process.

Antibiotic administration in the drinking water of mice.

PubMed

Marx, James O; Vudathala, Daljit; Murphy, Lisa; Rankin, Shelley; Hankenson, F Claire

2014-05-01

Although antibiotics frequently are added to the drinking water of mice, this practice has not been tested to confirm that antibiotics reach therapeutic concentrations in the plasma of treated mice. In the current investigation, we 1) tested the stability of enrofloxacin and doxycycline in the drinking water of adult, female C57BL/6 mice; 2) measured the mice's consumption of water treated with enrofloxacin, doxycycline, amoxicillin, or trimethoprim-sulfamethoxazole; and 3) used HPLC to measure plasma antibiotic concentrations in mice that had ingested treated water for 1 wk. Plasma concentrations of antibiotic were measured 1 h after the start of both the light and dark cycle. The main findings of the study were that both enrofloxacin and nonpharmaceutical, chemical-grade doxycycline remained relatively stable in water for 1 wk. In addition, mice consumed similar volumes of antibiotic-treated and untreated water. The highest plasma antibiotic concentrations measured were: enrofloxacin, 140.1 ± 10.4 ng/mL; doxycycline, 56.6 ± 12.5 ng/mL; amoxicillin, 299.2 ± 64.1 ng/mL; and trimethoprim-sulfamethoxazole, 5.9 ± 1.2 ng/mL. Despite the stability of the antibiotics in the water and predictable water consumption by mice, the plasma antibiotic concentrations were well below the concentrations required for efficacy against bacterial pathogens, except for those pathogens that are exquisitely sensitive to the antibiotic. The findings of this investigation prompt questions regarding the rationale of the contemporary practice of adding antibiotics to the drinking water of mice for systemic antibacterial treatments.

Ureaplasma serovars & their antimicrobial susceptibility in patients of infertility & genital tract infections.

PubMed

Dhawan, Benu; Malhotra, Neena; Sreenivas, Vishnubhatla; Rawre, Jyoti; Khanna, Neena; Chaudhry, Rama; Mittal, Suneeta

2012-12-01

Ureaplasmas have been implicated in a variety of clinical conditions. However, only certain serovars of ureaplasmas are disease associated. Only a few classes of antimicrobial agents are available for the treatment of mycoplasmal infections in humans. Increase of resistance of genital mycoplasmas to antimicrobials has been reported worldwide. The aim of the present study was to determine the occurrence of Ureaplasma serovars in patients with infertility and genital tract infections with polymerase chain reaction (PCR)-based serotyping. The antimicrobial susceptibilities of Ureaplasma spp. and Mycoplasma hominis were also assessed to determine the most suitable treatment strategy. Sexually active adults (n=147) with symptoms of genital tract infections and 115 infertile women were enrolled. Endocervical swabs from women and urethral swabs from men were subjected to culture and multiplex PCR for detection of genital mycoplasmas. Serotyping of Ureaplasma was done by PCR and antimicrobial susceptibility to doxycycline, azithromycin, josamycin and ofloxacin was done by microbroth dilution method. Ureaplasma was detected in 25.8 per cent patients with genital tract infections and 20.8 per cent in infertile women. Serovar 3/14 was the most frequent isolate followed by serovar 1 and serovar 6. The majority of Ureaplasma isolates were susceptible to doxycycline (91%) and josamycin (86%) followed by ofloxacin (77%) and azithromycin (71%). All the isolates of M. hominis were uniformly susceptible to doxycycline, josamycin and ofloxacin. The predominance of Ureaplasma serovar 3/14 suggests their possible pathogenic role in genital tract infections and infertility. For empirical treatment, doxycycline could be the drug of choice for genital mycoplasmas.

Antibiotic Administration in the Drinking Water of Mice

PubMed Central

Marx, James O; Vudathala, Daljit; Murphy, Lisa; Rankin, Shelley; Hankenson, F Claire

2014-01-01

Although antibiotics frequently are added to the drinking water of mice, this practice has not been tested to confirm that antibiotics reach therapeutic concentrations in the plasma of treated mice. In the current investigation, we 1) tested the stability of enrofloxacin and doxycycline in the drinking water of adult, female C57BL/6 mice; 2) measured the mice's consumption of water treated with enrofloxacin, doxycycline, amoxicillin, or trimethoprim–sulfamethoxazole; and 3) used HPLC to measure plasma antibiotic concentrations in mice that had ingested treated water for 1 wk. Plasma concentrations of antibiotic were measured 1 h after the start of both the light and dark cycle. The main findings of the study were that both enrofloxacin and nonpharmaceutical, chemical-grade doxycycline remained relatively stable in water for 1 wk. In addition, mice consumed similar volumes of antibiotic-treated and untreated water. The highest plasma antibiotic concentrations measured were: enrofloxacin, 140.1 ± 10.4 ng/mL; doxycycline, 56.6 ± 12.5 ng/mL; amoxicillin, 299.2 ± 64.1 ng/mL; and trimethoprim–sulfamethoxazole, 5.9 ± 1.2 ng/mL. Despite the stability of the antibiotics in the water and predictable water consumption by mice, the plasma antibiotic concentrations were well below the concentrations required for efficacy against bacterial pathogens, except for those pathogens that are exquisitely sensitive to the antibiotic. The findings of this investigation prompt questions regarding the rationale of the contemporary practice of adding antibiotics to the drinking water of mice for systemic antibacterial treatments. PMID:24827573

Impact of spores on the comparative efficacies of five antibiotics for treatment of Bacillus anthracis in an in vitro hollow fiber pharmacodynamic model.

PubMed

Louie, Arnold; VanScoy, Brian D; Brown, David L; Kulawy, Robert W; Heine, Henry S; Drusano, George L

2012-03-01

Bacillus anthracis, the bacterium that causes anthrax, is an agent of bioterrorism. The most effective antimicrobial therapy for B. anthracis infections is unknown. An in vitro pharmacodynamic model of B. anthracis was used to compare the efficacies of simulated clinically prescribed regimens of moxifloxacin, linezolid, and meropenem with the "gold standards," doxycycline and ciprofloxacin. Treatment outcomes for isogenic spore-forming and non-spore-forming strains of B. anthracis were compared. Against spore-forming B. anthracis, ciprofloxacin, moxifloxacin, linezolid, and meropenem reduced the B. anthracis population by 4 log(10) CFU/ml over 10 days. Doxycycline reduced the population of this B. anthracis strain by 5 log(10) CFU/ml (analysis of variance [ANOVA] P = 0.01 versus other drugs). Against an isogenic non-spore-forming strain, meropenem killed the vegetative B. anthracis the fastest, followed by moxifloxacin and ciprofloxacin and then doxycycline. Linezolid offered the lowest bacterial kill rate. Heat shock studies using the spore-producing B. anthracis strain showed that with moxifloxacin, ciprofloxacin, and meropenem therapies the total population was mostly spores, while the population was primarily vegetative bacteria with linezolid and doxycycline therapies. Spores have a profound impact on the rate and extent of killing of B. anthracis. Against spore-forming B. anthracis, the five antibiotics killed the total (spore and vegetative) bacterial population at similar rates (within 1 log(10) CFU/ml of each other). However, bactericidal antibiotics killed vegetative B. anthracis faster than bacteriostatic drugs. Since only vegetative-phase B. anthracis produces the toxins that may kill the infected host, the rate and mechanism of killing of an antibiotic may determine its overall in vivo efficacy. Further studies are needed to examine this important observation.

Systemic therapy of ocular and cutaneous rosacea in children.

PubMed

Gonser, L I; Gonser, C E; Deuter, C; Heister, M; Zierhut, M; Schaller, M

2017-10-01

In paediatric rosacea, ocular symptoms are often predominant. Literature about systemic therapy of paediatric ocular rosacea is sparse, though. Analysis of children with ocular rosacea treated systemically, particularly addressing remission and recurrence rates. Retrospective study reviewing the medical records of children with ocular rosacea treated with systemic antibiotic therapy. Nine of 19 patients were chosen for detailed analysis. To our knowledge, this is the first study in paediatric ocular rosacea requiring systemic therapy with a larger patient group and a longer follow-up (mean follow-up = 30.2 months). 17 patients (89.5%) suffered from blepharitis, 15 patients (78.9%) from conjunctivitis, twelve patients (63.2%) from chalazia/styes and nine female patients (47.4%) from corneal involvement. We used erythromycin (n = 9) or roxithromycin (n = 1) in patients younger than 8 years and doxycycline (n = 8) or minocycline (n = 1) in patients older than 8 years. Seven of nine patients treated with erythromycin, one of eight patients treated with doxycycline and the patient treated with minocycline achieved a complete remission of ocular and cutaneous symptoms. Two of nine patients treated with erythromycin, seven of eight patients treated with doxycycline and the patient treated with roxithromycin achieved a partial remission. Relapses occurred in the patient treated with minocycline (cutaneous), two of eight patients treated with doxycycline (ocular and cutaneous) and one of nine patients treated with erythromycin (cutaneous). To achieve a complete remission of cutaneous and ocular rosacea, a long-term anti-inflammatory treatment of at least 6 months is necessary. The relapse rates seem to be lower than in adults especially in the patients treated with erythromycin. © 2017 European Academy of Dermatology and Venereology.

Imaging the accumulation and suppression of tau pathology using multiparametric MRI

PubMed Central

Holmes, Holly E.; Colgan, Niall; Ismail, Ozama; Ma, Da; Powell, Nick M.; O'Callaghan, James M.; Harrison, Ian F.; Johnson, Ross A.; Murray, Tracey K.; Ahmed, Zeshan; Heggenes, Morton; Fisher, Alice; Cardoso, M.J.; Modat, Marc; Walker-Samuel, Simon; Fisher, Elizabeth M.C.; Ourselin, Sebastien; O'Neill, Michael J.; Wells, Jack A.; Collins, Emily C.; Lythgoe, Mark F.

2016-01-01

Mouse models of Alzheimer's disease have served as valuable tools for investigating pathogenic mechanisms relating to neurodegeneration, including tau-mediated and neurofibrillary tangle pathology—a major hallmark of the disease. In this work, we have used multiparametric magnetic resonance imaging (MRI) in a longitudinal study of neurodegeneration in the rTg4510 mouse model of tauopathy, a subset of which were treated with doxycycline at different time points to suppress the tau transgene. Using this paradigm, we investigated the sensitivity of multiparametric MRI to both the accumulation and suppression of pathologic tau. Tau-related atrophy was discernible from 5.5 months within the cortex and hippocampus. We observed markedly less atrophy in the treated rTg4510 mice, which was enhanced after doxycycline intervention from 3.5 months. We also observed differences in amide proton transfer, cerebral blood flow, and diffusion tensor imaging parameters in the rTg4510 mice, which were significantly less altered after doxycycline treatment. We propose that these non-invasive MRI techniques offer insight into pathologic mechanisms underpinning Alzheimer's disease that may be important when evaluating emerging therapeutics targeting one of more of these processes. PMID:26923415

Epizootic rabbit enteropathy inoculum (TEC4): antibiograms and antibiotic fractionation.

PubMed

Huybens, Nathalie; Houeix, Julien; Licois, Dominique; Mainil, Jacques; Marlier, Didier

2011-01-01

Epizootic rabbit enteropathy (ERE) emerged and spread in Europe within the last 13 years causing major economical loss. The aims of the study was to evaluate antibiograms of TEC4, an inoculum composed of an extract of intestinal content of affected rabbits, and to test the potential of different antibiotic-based TEC4 fractions to reproduce the disease. Twenty nine different antibiotic discs were incubated for determining bacteria resistance. In a complementary study, nine tubes of liquid medium were inoculated with TEC4, incubated and added individually with amoxicillin/clavulanic acid, bacitracin, ceftiofur, doxycycline, novobiocin, streptomycyin, tylosin, vancomycin and 0.9% saline solution as control. The content of each tube was washed by centrifugation and suspended in saline. The three most effective antibiotics are florfenicol, amoxycillin/clavulanic acid and tylosin. A high concentration of Clostridium sordelli and Bacillus firmus were isolated in all fractions. Species never cultured from TEC4 were identified as Fusobacterium necrogenes (in vancomycin fraction), Cellulomonas sp (in novobiocin fraction) and Bacteroides distasonis (in doxycycline fraction). The ERE was reproduced when bacitracin, doxycycline and 0.9% fractions were inoculated. Rabbits showed ERE clinical signs with the specific drop in daily weight gain.

New uses for older antibiotics. The 'rediscovery' of four beneficial and cost-effective antimicrobials.

PubMed

Cunha, B A

1997-04-01

Because of its intracellular mechanism of activity, excellent safety profile, and low cost, doxycycline is one of the most extensively used antibiotics in the world, and its use will increase as new applications are found. One of its most important uses is in treatment of bacterial community-acquired pneumonias, but it is also useful against atypical pneumonias and sexually transmitted disease. As zoonotic infections continue to increase around the world, doxycycline will occupy an increasingly prominent place. Minocycline shares doxycycline's favorable attributes and also has tissue-penetration characteristics that are important when therapeutic alternatives are few, as in MRSA. TMP-SMX is widely used to treat urinary and respiratory tract infections and for prophylaxis and treatment of P carinii infection. As the AIDS epidemic continues, its use will continue to grow, because it is also effective against other pathogens associated with AIDS. TMP-SMX is relatively underused for treating gram-negative bacteremias, especially nosocomial infections caused by nonaeruginosa pseudomonads. Metronidazole is a cost-effective antianaerobic component in treatment of intra-abdominal and pelvic infections, especially when it is combined with a once-a-day antibiotic.

Nanoparticle-stabilized liposomes for pH-responsive gastric drug delivery.

PubMed

Thamphiwatana, Soracha; Fu, Victoria; Zhu, Jingying; Lu, Diannan; Gao, Weiwei; Zhang, Liangfang

2013-10-01

We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However, when the stabilized liposomes are present in an environment with neutral pH, the gold stabilizers detach from the liposomes, resulting in free liposomes that can actively fuse with bacterial membranes. Using Helicobacter pylori as a model bacterium and doxycycline as a model antibiotic, we demonstrate such pH-responsive fusion activity and drug release profile of the nanoparticle-stabilized liposomes. Particularly, at neutral pH the gold nanoparticles detach, and thus the doxycycline-loaded liposomes rapidly fuse with bacteria and cause superior bactericidal efficacy as compared to the free doxycycline counterpart. Our results suggest that the reported liposome system holds a substantial potential for gastric drug delivery; it remains inactive (stable) in the stomach lumen but actively interacts with bacteria once it reaches the mucus layer of the stomach where the bacteria may reside.

Microscopic and clinical evidence for Anaplasma (Ehrlichia) phagocytophilum infection in Italian cats.

PubMed

Tarello, W

2005-06-11

Fifteen cats from Italy with Ehrlichia-like inclusion bodies in their neutrophils were studied. They were diagnosed with Anaplasma (Ehrlichia) phagocytophilum infection on the basis of cytological observation of morulae within 1 to 21 per cent of their neutrophils, clinical signs characteristic of ehrlichiosis and their response to doxycycline. The predominant signs of disease were anorexia, lethargy, hyperaesthesia, muscle and joint pain, lameness, neck rigidity, lymphadenomegaly, gingivitis/periodontitis, conjunctivitis, weight loss, incoordination, pale mucous membranes and hyperglobulinaemia. The cat with inclusions in 21 per cent of its neutrophils had suffered arthralgia, tachypnoea, neck rigidity, vomiting and thrombocytopenia for four months, but recovered promptly after treatment with doxycycline.

21 CFR 522.778 - Doxycycline hyclate.

Code of Federal Regulations, 2011 CFR

2011-04-01

... not use in dogs less than 1-year old. Use of tetracyclines during tooth development has been associated with permanent discoloration of teeth. Do not use in pregnant bitches. Use in breeding dogs has...] (d) Conditions of use—(1) Dogs—(i) Amount. Apply subgingivally to periodontal pocket(s) of affected...

21 CFR 522.778 - Doxycycline hyclate.

Code of Federal Regulations, 2012 CFR

2012-04-01

... not use in dogs less than 1-year old. Use of tetracyclines during tooth development has been associated with permanent discoloration of teeth. Do not use in pregnant bitches. Use in breeding dogs has...] (d) Conditions of use—(1) Dogs—(i) Amount. Apply subgingivally to periodontal pocket(s) of affected...

21 CFR 522.778 - Doxycycline hyclate.

Code of Federal Regulations, 2013 CFR

2013-04-01

... not use in dogs less than 1-year old. Use of tetracyclines during tooth development has been associated with permanent discoloration of teeth. Do not use in pregnant bitches. Use in breeding dogs has...] (d) Conditions of use—(1) Dogs—(i) Amount. Apply subgingivally to periodontal pocket(s) of affected...

21 CFR 522.778 - Doxycycline hyclate.

Code of Federal Regulations, 2010 CFR

2010-04-01

...] (d) Conditions of use—(1) Dogs—(i) Amount. Apply subgingivally to periodontal pocket(s) of affected teeth. (ii) Indications for use. For treatment and control of periodontal disease. (iii) Limitations. Do not use in dogs less than 1-year old. Use of tetracyclines during tooth development has been...

Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

PubMed Central

Ham, Claire; Ferguson, Deborah; Tudor, Hannah; Mattiuzzo, Giada; Klaver, Bep; Page, Mark; Stebbings, Richard; Das, Atze T.; Berkhout, Ben; Almond, Neil; Cranage, Martin P.

2016-01-01

In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity. PMID:28002473

Impact of Spores on the Comparative Efficacies of Five Antibiotics for Treatment of Bacillus anthracis in an In Vitro Hollow Fiber Pharmacodynamic Model

PubMed Central

VanScoy, Brian D.; Brown, David L.; Kulawy, Robert W.; Heine, Henry S.; Drusano, George L.

2012-01-01

Bacillus anthracis, the bacterium that causes anthrax, is an agent of bioterrorism. The most effective antimicrobial therapy for B. anthracis infections is unknown. An in vitro pharmacodynamic model of B. anthracis was used to compare the efficacies of simulated clinically prescribed regimens of moxifloxacin, linezolid, and meropenem with the “gold standards,” doxycycline and ciprofloxacin. Treatment outcomes for isogenic spore-forming and non-spore-forming strains of B. anthracis were compared. Against spore-forming B. anthracis, ciprofloxacin, moxifloxacin, linezolid, and meropenem reduced the B. anthracis population by 4 log10 CFU/ml over 10 days. Doxycycline reduced the population of this B. anthracis strain by 5 log10 CFU/ml (analysis of variance [ANOVA] P = 0.01 versus other drugs). Against an isogenic non-spore-forming strain, meropenem killed the vegetative B. anthracis the fastest, followed by moxifloxacin and ciprofloxacin and then doxycycline. Linezolid offered the lowest bacterial kill rate. Heat shock studies using the spore-producing B. anthracis strain showed that with moxifloxacin, ciprofloxacin, and meropenem therapies the total population was mostly spores, while the population was primarily vegetative bacteria with linezolid and doxycycline therapies. Spores have a profound impact on the rate and extent of killing of B. anthracis. Against spore-forming B. anthracis, the five antibiotics killed the total (spore and vegetative) bacterial population at similar rates (within 1 log10 CFU/ml of each other). However, bactericidal antibiotics killed vegetative B. anthracis faster than bacteriostatic drugs. Since only vegetative-phase B. anthracis produces the toxins that may kill the infected host, the rate and mechanism of killing of an antibiotic may determine its overall in vivo efficacy. Further studies are needed to examine this important observation. PMID:22155821

Elevated levels of von Willebrand factor and high mobility group box 1 (HMGB1) are associated with disease severity and clinical outcome of scrub typhus.

PubMed

Chen, Hongliu; Ning, Zong; Qiu, Ying; Liao, Yuanli; Chang, Haihua; Ai, Yuanyuan; Wei, Yinghua; Deng, Yiming; Shen, Ying

2017-08-01

This study aimed to investigate whether von Willebrand factor (vWF) and high mobility group box 1 (HMGB1) are associated with the severity and clinical outcome of scrub typhus and to seek novel biomarkers for surveillance and prediction of the prognosis of this infection. Serum concentrations of vWF and HMGB1 were measured twice by ELISA for scrub typhus patients (n=103), once prior to doxycycline therapy and then on day 7 of doxycycline therapy; concentrations were measured once for healthy controls (n=32). Among the total 103 patients enrolled, 38 had disease complicated by multiple organ dysfunction syndrome (MODS). Serum concentrations of vWF and HMGB1 were significantly higher in all the patients than in the healthy controls, both prior to doxycycline treatment and on day 7 of doxycycline treatment (p<0.01). Furthermore, serum levels of vWF, HMGB1, and creatinine (SCr) in the patients with MODS increased distinctly, while the platelet (PLT) count diminished markedly compared to the levels in patients without MODS (p<0.01). The concentration of vWF was positively correlated with that of HMGB1 (r=0.764, p<0.001) and SCr (r=0.528, p<0.001), but negatively correlated with the PLT count (r=-0.632, p<0.001). Both HMGB1 and vWF were significantly associated with mortality in scrub typhus (area under the curve (AUC)=0.864, p=0.001, and AUC=0.862, p=0.001, respectively). Elevated levels of vWF and HMGB1 are associated with the severity and clinical outcome of scrub typhus. These represent possible new biomarkers for use in the assessment and prognostic prediction of this infection. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Expression of BCL-2 in liver grafts after adenoviral transfer improves survival following prolonged ischemia and reperfusion in rat liver transplantation.

PubMed

Kienle, K; Rentsch, M; Müller, T; Engelhard, N; Vogel, M; Jauch, K W; Beham, A

2005-01-01

Apoptosis represents a crucial mechanism of ischemia-reperfusion injury after liver transplantation. Bcl-2 may inhibit apoptosis. This study investigates the effect on ischemia/reperfusion injury and survival after rat liver transplantation of adenoviral bcl-2 transfer into donor livers. A nonreplicative adenovirus, expressing bcl-2 under control of a tetracyclin-inducible promoter (adv TetOn bcl-2) was used to treat male Lewis rats in combination with a second adenovirus transferring the TetOn repressor protein under control of a cytomegalovirus promoter (advCMVRep). Virus induction was achieved by addition of doxycyclin to the drinking water. Controls were pretreated with a control adenovirus (advCMV GFP) or with doxycycline. Liver transplantations were performed after 16-hour graft storage. Bcl-2 expression was evaluated by Western blot and immunohistology. Survival was monitored for 7 days, and tissue specimens were collected at 24 hours and 7 days post reperfusion. After pretreatment with advTetOn bcl-2/adv CMVRep, intrahepatic bcl-2 expression was evident at 24 hours and 7 days but was absent among controls. Bcl-2 expression was detected in hepatocytes and, to a high degree, in sinusoidal lining cells. TUNEL-positive sinusoidal lining cells were strikingly reduced after bcl-2 transfer (0.1 +/- 0.3 cells/hpf, mean +/- SD) compared to control virus (4.8 +/- 2.3) or doxycyclin-treated grafts (1.3 +/- 0.2); P < .05. After bcl-2 treatment, survival after transplantation was 100%, whereas it was 50% in both control groups (P = .035). The study shows the feasibility of transient, doxycyclin-controlled adenoviral gene transfer in a transplantation model. Bcl-2 expression increased survival after ischemia/reperfusion in rat liver transplantation, potentially through protection of sinusoidal lining cells.

Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein, Tat, in the CNS.

PubMed

Paris, Jason J; Fenwick, Jason; McLaughlin, Jay P

2014-05-01

Increased anxiety is co-morbid with human immunodeficiency virus (HIV) infection. Actions of the neurotoxic HIV-1 regulatory protein, Tat, may contribute to affective dysfunction. We hypothesized that Tat expression would increase anxiety-like behavior of female GT-tg bigenic mice that express HIV-1 Tat protein in the brain in a doxycycline-dependent manner. Furthermore, given reports that HIV-induced anxiety may occur at lower rates among women, and that the neurotoxic effects of Tat are ameliorated by sex steroids in vitro, we hypothesized that 17β-estradiol and/or progesterone would ameliorate Tat-induced anxiety-like effects. Among naturally-cycling proestrous and diestrous mice, Tat-induction via 7days of doxycycline treatment significantly increased anxiety-like responding in an open field, elevated plus maze and a marble-burying task, compared to treatment with saline. Proestrous mice demonstrated less anxiety-like behavior than diestrous mice in the open field and elevated plus maze, but these effects did not significantly interact with Tat-induction. Among ovariectomized mice, doxycycline-induced Tat protein significantly increased anxiety-like behavior in an elevated plus maze and a marble burying task compared to saline-treated mice, but not an open field (where anxiety-like responding was already maximal). Co-administration of progesterone (4mg/kg), but not 17β-estradiol (0.09mg/kg), with doxycycline significantly ameliorated anxiety-like responding in the elevated plus maze and marble burying tasks. When administered together, 17β-estradiol partially antagonized the protective effects of progesterone on Tat-induced anxiety-like behavior. These findings support evidence of steroid-protection over HIV-1 proteins, and extend them by demonstrating the protective capacity of progesterone on Tat-induced anxiety-like behavior of ovariectomized female mice. Copyright © 2014 Elsevier Inc. All rights reserved.

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library

PubMed Central

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G.; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10–20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

PubMed

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

Matrix metalloproteinase (MMP)-2 decreases calponin-1 levels and contributes to arterial remodeling in early hypertension.

PubMed

Belo, Vanessa de Almeida; Parente, Juliana Montenegro; Tanus-Santos, José Eduardo; Castro, Michele M

2016-10-15

Increased matrix metalloproteinase (MMP)-2 is implicated in the vascular remodeling of hypertension. Calponin-1 is a contractile protein, and its absence is associated with vascular smooth muscle cell (VSMC) phenotype switch, which leads to migration and remodeling. We evaluated whether increased MMP-2 activity precedes chronic vascular remodeling by decreasing calponin-1 and inducing VSMC proliferation. Sham or two kidney-one clip (2K1C) rats were treated with doxycycline at 30mg/kg/day. Systolic blood pressure was increased in the 2K1C rats after 1 and 2weeks post-surgery, and doxycycline was effective to reduce it only at 2weeks of hypertension (p<0.05). Increased activity of MMP-2 was observed in aortas from 2K1C at 1 and 2weeks of hypertension, followed by increased VSMC proliferation, and those effects were abolished by treating 2K1C rats with doxycycline (p<0.05). Increased aortic media to lumen ratio started to emerge in 2K1C rats at 1week of hypertension, and it was established by 2weeks. MMP-2 and calponin-1 co-localized in the cytosol of VSMC. Aortas from 2K1C rats showed a significant reduction in calponin-1 levels at 1week of hypertension, and doxycycline prevented its loss (p<0.05). However, at 2weeks of hypertension, calponin-1 was upregulated in 2K1C (p<0.05 vs. Sham groups). The mRNA levels of calponin-1 were not altered in the aortas of 2K1C at 1week of hypertension. MMP-2 may contribute to the post-translational decrease in calponin-1, thus culminating in hypertension-induced maladaptive arterial remodeling. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of Minocycline Susceptibility Testing Methods for Carbapenem-Resistant Acinetobacter baumannii.

PubMed

Wang, Peng; Bowler, Sarah L; Kantz, Serena F; Mettus, Roberta T; Guo, Yan; McElheny, Christi L; Doi, Yohei

2016-12-01

Treatment options for infections due to carbapenem-resistant Acinetobacter baumannii are extremely limited. Minocycline is a semisynthetic tetracycline derivative with activity against this pathogen. This study compared susceptibility testing methods that are used in clinical microbiology laboratories (Etest, disk diffusion, and Sensititre broth microdilution methods) for testing of minocycline, tigecycline, and doxycycline against 107 carbapenem-resistant A. baumannii clinical isolates. Susceptibility rates determined with the standard broth microdilution method using cation-adjusted Mueller-Hinton (MH) broth were 77.6% for minocycline and 29% for doxycycline, and 92.5% of isolates had tigecycline MICs of ≤2 μg/ml. Using MH agar from BD and Oxoid, susceptibility rates determined with the Etest method were 67.3% and 52.3% for minocycline, 21.5% and 18.7% for doxycycline, and 71% and 29.9% for tigecycline, respectively. With the disk diffusion method using MH agar from BD and Oxoid, susceptibility rates were 82.2% and 72.9% for minocycline and 34.6% and 34.6% for doxycycline, respectively, and rates of MICs of ≤2 μg/ml were 46.7% and 23.4% for tigecycline. In comparison with the standard broth microdilution results, very major rates were low (∼2.8%) for all three drugs across the methods, but major error rates were higher (∼5.6%), especially with the Etest method. For minocycline, minor error rates ranged from 14% to 37.4%. For tigecycline, minor error rates ranged from 6.5% to 69.2%. The majority of minor errors were due to susceptible results being reported as intermediate. For minocycline susceptibility testing of carbapenem-resistant A. baumannii strains, very major errors are rare, but major and minor errors overcalling strains as intermediate or resistant occur frequently with susceptibility testing methods that are feasible in clinical laboratories. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Diet Influences Expression of Autoimmune Associated Genes and Disease Severity By Epigenetic Mechanisms in a Transgenic Lupus Model

PubMed Central

Strickland, Faith M.; Hewagama, Anura; Wu, Ailing; Sawalha, Amr H.; Delaney, Colin; Hoeltzel, Mark F.; Yung, Raymond; Johnson, Kent; Mickelson, Barbara; Richardson, Bruce C.

2013-01-01

Objective Lupus flares when genetically predisposed people encounter appropriate environmental agents. Current evidence indicates that the environment contributes by inhibiting T cell DNA methylation, causing overexpression of normally silenced genes. DNA methylation depends on both dietary transmethylation micronutrients and Erk-regulated DNA methyltransferase 1 (Dnmt1) levels. We used transgenic mice to study interactions between diet, Dnmt1 levels and genetic predisposition on the development and severity of lupus. Methods A doxycycline-inducible Erk defect was bred into lupus-resistant (C57BL/6) or lupus-susceptible (C57BL/6xSJL) mouse strains. Doxycycline treated mice were fed a standard commercial diet for eighteen weeks then switched to diets supplemented(MS) or restricted(MR) intransmethylation micronutrients. Disease severity was assessed by anti-dsDNA antibodies, proteinuria, hematuria and histopathology of kidney tissues. Pyrosequencing was used to determine micronutrient effects on DNA methylation. Results Doxycycline induced modest levels of anti-dsDNA antibodies in C57BL/6 mice and higher levels in C57BL/6xSJL mice. Doxycycline-treated C57BL/6xSJL mice developed hematuria and glomerulonephritis on the MR and standard but not the MS diet. In contrast C57BL/6 mice developed kidney disease only on the MR diet. Decreasing Erk signaling and methyl donors also caused demethylation and overexpression of the CD40lg gene in female mice, consistent with demethylation of the second X chromosome. Both the dietary methyl donor content and duration of treatment influenced methylation and expression of the CD40lg gene. Conclusions Dietary micronutrients that affect DNA methylation can exacerbate or ameliorate SLE disease in this transgenic murine lupus model, and contribute to lupus susceptibility and severity through genetic/epigenetic interactions. PMID:23576011

[Non-viral sexually transmitted infections - Epidemiology, clinical manifestations, diagnostics and therapy : Part 2: Chlamydia and mycoplasma].

PubMed

Nenoff, P; Manos, A; Ehrhard, I; Krüger, C; Paasch, U; Helmbold, P; Handrick, W

2017-01-01

Chlamydia trachomatis is the most common pathogen of sexually transmitted bacterial infections worldwide. Every year in Germany approximately 300,000 new infections are to be expected. Chlamydia infections occur nearly exclusively in the postpubertal period. The peak age group is 15-25 years. The infection usually runs an asymptomatic course and the diagnosis is made by nucleic acid amplification techniques (NAAT) often after chlamydial screening or if complications occur. For treatment of chlamydial infections oral doxycycline 100 mg twice daily over 7 days is initially used or alternatively oral azithromycin 1.5 g as a single dose is recommended. The sexual partner should also be investigated and treated. Genital Mycoplasma infections are caused by Ureaplasma urealyticum (pathogen of urethritis and vaginitis), Ureaplasma parvum (mostly saprophytic and rarely a cause of urethritis) and Mycoplasma hominis (facultative pathogenic). Mycoplasma genitalium represents a relatively new sexually transmitted Mycoplasma species. Doxycycline is effective in Ureaplasma infections or alternatively clarithromycin and azithromycin. Doxycycline can be ineffective in Mycoplasma hominis infections and an alternative is clindamycin. Non-gonococcal and non-chlamydial urethritis due to Mycoplasma genitalium can now be diagnosed by molecular biological techniques using PCR and should be treated by azithromycin.

Enriched Astaxanthin Extract from Haematococcus pluvialis Augments Growth Factor Secretions to Increase Cell Proliferation and Induces MMP1 Degradation to Enhance Collagen Production in Human Dermal Fibroblasts

PubMed Central

Chou, Hsin-Yu; Lee, Chelsea; Pan, Jian-Liang; Wen, Zhi-Hong; Huang, Shu-Hung; Lan, Chi-Wei John; Liu, Wang-Ta; Hour, Tzyh-Chyuan; Hseu, You-Cheng; Hwang, Byeong Hee; Cheng, Kuo-Chen; Wang, Hui-Min David

2016-01-01

Among many antioxidants that are used for the repairing of oxidative stress induced skin damages, we identified the enriched astaxanthin extract (EAE) from Haematococcus pluvialis as a viable ingredient. EAE was extracted from the red microalgae through supercritical fluid carbon dioxide extraction. To compare the effectiveness, EAE wastreated on human dermal fibroblasts with other components, phorbol 12-myristate 13-acetate (PMA), and doxycycline. With sirius red staining and quantitative real-time polymerase chain reaction (qRT-PCR), we found that PMA decreased the collagen concentration and production while overall the addition of doxycycline and EAE increased the collagen concentration in a trial experiments. EAE increased collagen contents through inhibited MMP1 and MMP3 mRNA expression and induced TIMP1, the antagonists of MMPs protein, gene expression. As for when tested for various proteins through western blotting, it was seen that the addition of EAE increased the expression of certain proteins that promote cell proliferation. Testing those previous solutions using growth factor assay, it was noticeable that EAE had a positive impact on cell proliferation and vascular endothelial growth factor (VEGF) than doxycycline, indicating that it was a better alternative treatment for collagen production. To sum up, the data confirmed the possible applications as medical cosmetology agentsand food supplements. PMID:27322248

17 β-estradiol mineralization in human waste products and soil in the presence and the absence of antimicrobials.

PubMed

Amarakoon, Inoka; Farenhorst, Annemieke; Rose, Karin; Claeys, Anne; Ascef, Bruna

2016-10-02

Natural steroidal estrogens, such as 17 β-estradiol (E2), as well as antimicrobials such as doxycycline and norfloxacin, are excreted by humans and hence detected in sewage sludge and biosolid. The disposal of human waste products on agricultural land results in estrogens and antibiotics being detected as mixtures in soils. The objective of this study was to examine microbial respiration and E2 mineralization in sewage sludge, biosolid, and soil in the presence and the absence of doxycycline and norfloxacin. The antimicrobials were applied to the media either alone or in combination at total rates of 4 and 40 mg kg -1 , with the 4 mg kg -1 rate being an environmentally relevant concentration. The calculated time that half of the applied E2 was mineralized ranged from 294 to 418 days in sewage sludge, from 721 to 869 days in soil, and from 2,258 to 14,146 days in biosolid. E2 mineralization followed first-order and the presence of antimicrobials had no significant effect on mineralization half-lives, except for some antimicrobial applications to the human waste products. At 189 day, total E2 mineralization was significantly greater in sewage sludge (38 ±0.7%) > soil (23 ±0.7%) > biosolid (3 ±0.7%), while total respiration was significantly greater in biosolid (1,258 mg CO 2 ) > sewage sludge (253 mg CO 2 ) ≥ soil (131 mg CO 2 ). Strong sorption of E2 to the organic fraction in biosolid may have resulted in reduced E2 mineralization despite the high microbial activity in this media. Total E2 mineralization at 189 day was not significantly influenced by the presence of doxycycline and/or norfloxacin in the media. Antimicrobial additions also did not significantly influence total respiration in media, except that total CO 2 respiration at 189 day was significantly greater for biosolid with 40 mg kg -1 doxycycline added, relative to biosolid without antimicrobials. We conclude that it is unlikely for doxycycline and norfloxacin, or their mixtures, to

Resistance to non-quinolone antimicrobials in commensal Escherichia coli isolates from chickens treated orally with enrofloxacin.

PubMed

Jurado, Sonia; Medina, Alberto; de la Fuente, Ricardo; Ruiz-Santa-Quiteria, José A; Orden, José A

2015-11-01

The aim of the present study was evaluate how oral administration of enrofloxacin affected the frequency of resistance to different antimicrobials in commensal Escherichia coli isolates from healthy chickens. A further objective of this study was to characterize the mechanisms of resistance in these isolates. A trend towards increased resistance to enrofloxacin, doxycycline and amoxicillin of E. coli isolates from chickens after enrofloxacin administration was observed. The increase in the resistance to doxycycline and amoxicillin was probably due to a co-selection of tetracycline and β-lactam resistance genes by the administration of enrofloxacin. The detection of tetM was much higher than expected (50%), which indicates that this gene may play an important role in tetracycline resistance in E. coli from chickens.

Modified Polymeric Nanoparticles Exert In Vitro Antimicrobial Activity Against Oral Bacteria.

PubMed

Toledano-Osorio, Manuel; Babu, Jegdish P; Osorio, Raquel; Medina-Castillo, Antonio L; García-Godoy, Franklin; Toledano, Manuel

2018-06-14

Polymeric nanoparticles were modified to exert antimicrobial activity against oral bacteria. Nanoparticles were loaded with calcium, zinc and doxycycline. Ions and doxycycline release were measured by inductively coupled plasma optical emission spectrometer and high performance liquid chromatography. Porphyromonas gingivalis , Lactobacillus lactis , Streptoccocus mutans , gordonii and sobrinus were grown and the number of bacteria was determined by optical density. Nanoparticles were suspended in phosphate-buffered saline (PBS) at 10, 1 and 0.1 mg/mL and incubated with 1.0 mL of each bacterial suspension for 3, 12, and 24 h. The bacterial viability was assessed by determining their ability to cleave the tetrazolium salt to a formazan dye. Data were analyzed by ANOVA and Scheffe’s F ( p < 0.05). Doxycycline doping efficacy was 70%. A burst liberation effect was produced during the first 7 days. After 21 days, a sustained release above 6 µg/mL, was observed. Calcium and zinc liberation were about 1 and 0.02 µg/mL respectively. The most effective antibacterial material was found to be the Dox-Nanoparticles (60% to 99% reduction) followed by Ca-Nanoparticles or Zn-Nanoparticles (30% to 70% reduction) and finally the non-doped nanoparticles (7% to 35% reduction). P. gingivalis , S. mutans and L. lactis were the most susceptible bacteria, being S. gordonii and S. sobrinus the most resistant to the tested nanoparticles.

Differential Top10 promoter regulation by six tetracycline analogues in plant cells

NASA Technical Reports Server (NTRS)

Love, John; Allen, George C.; Gatz, Christiane; Thompson, William F.; Brown, C. S. (Principal Investigator)

2002-01-01

The effects of five tetracycline analogues, anhydrotetracycline, doxycycline, minocycline, oxytetracycline, and tetracycline, on Top10 promoter activity in NT1 tobacco tissue culture cells have been analysed. The concentration that repressed Top10 promoter activity, the level of transgene repression and the kinetics of transgene de-repression were determined for each analogue, and could not be predicted from in vitro binding affinity to the tetracycline repressor or from comparison with animal cells. Doxycycline had the most potent effect on the Top10 promoter and completely inhibited transgene expression at 4 nmol l(-1). Tetracycline was the most versatile of the analogues tested; tetracycline inhibited the Top10 promoter at 10 nmol l(-1) and was easily washed out to restore Top10-driven expression in 12-24 h. A study was also made of the suitability for plant research of a novel tetracycline analogue, GR33076X. In animal cells, GR33076X de-repressed Top10 promoter activity in the presence of inhibitory concentrations of anhydrotetracycline. In NT1, it is shown that GR 33076X can antagonize repression of the Top10 promoter in the presence of tetracycline, but not of anhydrotetracycline or of doxycycline. Different tetracycline analogues can therefore be used to regulate the Top10 promoter in plant cells and this property may be exploited in planning an optimum course of transgene regulation.

Differential Top10 promoter regulation by six tetracycline analogues in plant cells.

PubMed

Love, John; Allen, George C; Gatz, Christiane; Thompson, William F

2002-09-01

The effects of five tetracycline analogues, anhydrotetracycline, doxycycline, minocycline, oxytetracycline, and tetracycline, on Top10 promoter activity in NT1 tobacco tissue culture cells have been analysed. The concentration that repressed Top10 promoter activity, the level of transgene repression and the kinetics of transgene de-repression were determined for each analogue, and could not be predicted from in vitro binding affinity to the tetracycline repressor or from comparison with animal cells. Doxycycline had the most potent effect on the Top10 promoter and completely inhibited transgene expression at 4 nmol l(-1). Tetracycline was the most versatile of the analogues tested; tetracycline inhibited the Top10 promoter at 10 nmol l(-1) and was easily washed out to restore Top10-driven expression in 12-24 h. A study was also made of the suitability for plant research of a novel tetracycline analogue, GR33076X. In animal cells, GR33076X de-repressed Top10 promoter activity in the presence of inhibitory concentrations of anhydrotetracycline. In NT1, it is shown that GR 33076X can antagonize repression of the Top10 promoter in the presence of tetracycline, but not of anhydrotetracycline or of doxycycline. Different tetracycline analogues can therefore be used to regulate the Top10 promoter in plant cells and this property may be exploited in planning an optimum course of transgene regulation.

An inducible tool for random mutagenesis in Aspergillus niger based on the transposon Vader.

PubMed

Paun, Linda; Nitsche, Benjamin; Homan, Tim; Ram, Arthur F; Kempken, Frank

2016-07-01

The ascomycete Aspergillus niger is widely used in the biotechnology, for instance in producing most of the world's citric acid. It is also known as a major food and feed contaminant. While generation of gene knockouts for functional genomics has become feasible in ku70 mutants, analyzing gene functions or metabolic pathways remains a laborious task. An unbiased transposon-based mutagenesis approach may aid this process of analyzing gene functions by providing mutant libraries in a short time. The Vader transposon is a non-autonomous DNA-transposon, which is activated by the homologous tan1-transposase. However, in the most commonly used lab strain of A. niger (N400 strain and derivatives), we found that the transposase, encoded by the tan1 gene, is mutated and inactive. To establish a Vader transposon-based mutagenesis system in the N400 background, we expressed the functional transposase of A. niger strain CBS 513.88 under the control of an inducible promoter based on the Tet-on system, which is activated in the presence of the antibiotic doxycycline (DOX). Increasing amounts of doxycycline lead to higher Vader excision frequencies, whereas little to none activity of Vader was observed without addition of doxycycline. Hence, this system appears to be suitable for producing stable mutants in the A. niger N400 background.

Leptospirosis presenting as honeymoon fever.

PubMed

de Sainte Marie, B; Delord, M; Dubourg, G; Gautret, P; Parola, P; Brouqui, P; Lagier, J C

2015-05-01

An increasing number of travelers from western countries visit tropical regions, questioning western physicians on the prophylaxis, the diagnosis and the therapeutic management of patients with travel-associated infection. In July 2014, a French couple stayed for an adventure-travel in Columbia without malaria prophylaxis. A week after their return the woman presented with fever, myalgia, and retro-orbital pain. Three days later, her husband presented similar symptoms. In both patients, testing for malaria, arboviruses and blood cultures remained negative. An empirical treatment with doxycycline and ceftriaxone was initiated for both patients. Serum collected from the female patient yielded positive IgM for leptospirosis but was negative for her husband. Positive Real-Time PCR were observed in blood and urine from both patients, confirming leptospirosis. Three lessons are noteworthy from this case report. First, after exclusion of malaria, as enteric fever, leptospirosis and rickettsial infection are the most prevalent travel-associated infections, empirical treatment with doxycycline and third generation cephalosporin should be considered. In addition, the diagnosis of leptospirosis requires both serology and PCR performed in both urine and blood samples. Finally, prophylaxis using doxycycline, also effective against leptospirosis, rickettsial infections or travellers' diarrhea should be recommended for adventure travelers in malaria endemic areas. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Borrelia miyamotoi infection presenting as human granulocytic anaplasmosis: a case report.

PubMed

Chowdri, Hanumara Ram; Gugliotta, Joseph L; Berardi, Victor P; Goethert, Heidi K; Molloy, Philip J; Sterling, Sherri L; Telford, Sam R

2013-07-02

The diverse tickborne infections of the northeastern United States can present as undifferentiated flu-like illnesses. In areas endemic for Lyme and other tickborne diseases, patients presenting with acute febrile illness with myalgia, headache, neutropenia, thrombocytopenia, and elevated hepatic aminotransferase levels are presumptively diagnosed as having human granulocytic anaplasmosis (HGA). To assign a cause for illness experienced by 2 case patients who were initially diagnosed with HGA but did not rapidly defervesce with doxycycline treatment and had no laboratory evidence of Anaplasma phagocytophilum infection. Case report. 2 primary care medical centers in Massachusetts and New Jersey. 2 case patients acutely presenting with fever. Identification of the causative agent by polymerase chain reaction and DNA sequencing. Molecular diagnostic assays detected Borrelia miyamotoi in the peripheral blood of both patients. There was no evidence of infection with other tickborne pathogens commonly diagnosed in the referral areas. One of the case patients may have had concurrent Lyme disease. The presence of B. miyamotoi DNA in the peripheral blood and the patients' eventual therapeutic response to doxycycline are consistent with the hypothesis that their illness was due to this newly recognized spirochete. Samples from tick-exposed patients acutely presenting with signs of HGA but who have a delayed response to doxycycline therapy or negative confirmatory test results for HGA should be analyzed carefully for evidence of B. miyamotoi infection.

Reconnaissance of selected PPCP compounds in Costa Rican surface waters.

PubMed

Spongberg, Alison L; Witter, Jason D; Acuña, Jenaro; Vargas, José; Murillo, Manuel; Umaña, Gerardo; Gómez, Eddy; Perez, Greivin

2011-12-15

Eighty-six water samples were collected in early 2009 from Costa Rican surface water and coastal locations for the analysis of 34 pharmaceutical and personal care product compounds (PPCPs). Sampling sites included areas receiving treated and untreated wastewaters, and urban and rural runoff. PPCPs were analyzed using a combination of solid phase extraction and liquid chromatography tandem mass spectrometry. The five most frequently detected compounds were doxycycline (77%), sulfadimethoxine (43%), salicylic acid (41%), triclosan (34%) and caffeine (29%). Caffeine had the maximum concentration of 1.1 mg L(-1), possibly due to coffee bean production facilities upstream. Other compounds found in high concentrations include: doxycycline (74 μg L(-1)), ibuprofen (37 μg L(-1)), gemfibrozil (17 μg L(-1)), acetominophen (13 μg L(-1)) and ketoprofen (10 μg L(-1)). The wastewater effluent collected from an oxidation pond had similar detection and concentrations of compounds compared to other studies reported in the literature. Waters receiving runoff from a nearby hospital showed higher concentrations than other areas for many PPCPs. Both caffeine and carbamazepine were found in low frequency compared to other studies, likely due to enhanced degradation and low usage, respectively. Overall concentrations of PPCPs in surface waters of Costa Rica are inline with currently reported occurrence data from around the world, with the exception of doxycycline. Published by Elsevier Ltd.

Effect of tetracyclines and 4-epiderivatives on the ureter

PubMed Central

Arrigoni, E.; Benzi, G.; Ferrara, A.

1972-01-01

1. The effect of tetracyclines on the isolated dog ureter is dependent on: (a) the tetracyclines used—mepicycline and doxycycline antagonizing, and tetracycline and rolitetracycline increasing the contractor action of barium chloride; (b) the percentage of 4-epiderivatives in the tetracyclines used—the higher the epiderivative concentration, the smaller the effect of mepicycline or doxycycline, and the greater the action of tetracycline or rolitetracycline. 2. In vivo the addition of the antibiotics into the renal pelvis shows no significant differences between the various tetracyclines or different 4-epiderivative concentrations on the intra-ureteral flow of the dog or guinea-pig. 3. Intravenous injection of mepicycline or doxycycline does not induce a significant change in the intra-ureteral flow, while intravenous administration of tetracycline or rolitetracycline produces a triphasic response: (a) a marked decrease of the intra-ureteral flow for a few minutes; (b) a return to the control condition for 30-60 min; and (c) a lesser but persistent decrease in flow for 60-120 minutes. In the first phase the ureteral smooth muscle is directly affected by the antibiotics circulating in the blood, while in the third phase the tetracyclines act via the intra-ureteral mucosa. 4. Neurogenic effects on the ureter-bladder junction in vivo are not affected by the tetracyclines tested. PMID:4625269

Micronucleus frequency in women with genital Chlamydia Trachomatis infection before and after therapy.

PubMed

Dimitrijević, A; Milosević-Djordjević, O; Grujicić, D; Arsenijević, S

2006-09-19

The main aim of the present study was to investigate the influence of infection with the intracellular bacterium Chlamydia trachomatis, and subsequent treatments with oral doxycycline or azithromycin on the frequency of micronuclei (MN) in peripheral blood lymphocytes of adult female patients receiving standard doses of these drugs. The frequency of micronuclei was measured in the lymphocytes of 38 newly diagnosed adult women with genital C. trachomatis infection. Samples were taken before and after the therapy, and from 50 healthy control females. The therapy was taken orally during 10 days at 2 x 100 mg per day, and then for another 10 days at 1 x 100 mg per day for doxycycline, and as a single dose of 1g for azithromycin. Isolated lymphocytes from all subjects were cultured by use of the whole-blood method and blocked in metaphase with cytochalasin B (Cyt B). One thousand binucleate cells per subject were scored according to published criteria. The frequency of micronuclei was not significantly higher in samples of infected females before therapy, compared with the baseline frequency in healthy control females (p > 0.05). In patients who received doxycycline, the micronucleus frequency after the end of therapy was significantly higher than before treatment (p < 0.001). The mean frequency of micronuclei in females after the end of the therapy with azithromycin did not show an increase (p > 0.05). The application of linear regression analysis showed that the difference in micronucleus frequency before and after therapy (effect of the antibiotics) was affected by the therapy type. Age and smoking did not affect micronucleus frequency in analyzed samples of patients (p = 0.078, 0.579). We conclude that C. trachomatis infection does not induce micronuclei in peripheral blood lymphocytes of infected adult female patients. Therapy with doxycycline significantly increases the micronucleus frequency in lymphocytes of treated patients, but treatment with azithromycin does

Indian tick typhus presenting with gangrene: a case report from an urban slum of Delhi.

PubMed

Kumar, Manish; Singh, Raghvendra; Yadav, Mukesh

2014-01-01

Indian Tick Typhus has been rarely reported in children from Delhi. A 10-y-old male child from Delhi presented with fever, non specific gastrointestinal symptoms, petechial rash and gangrene of all the toes. Possibility of rickettsial infection was entertained after the child failed to improve with best of the antibiotics. Sample for serology for rickettsial infection was sent and Doxycycline was started empirically. He became afebrile within 72 h of starting Doxycycline. Later, diagnosis of Indian Tick Typhus was confirmed on the basis of IgM positivity against Rickettsia conori. Possibility of rickettsial infection should be entertained in children with history of fever and skin rash, especially if the child fails to improve with a course of antibiotics and common infectious etiologies have been ruled out.

HILIC separation mechanisms of tetracyclines on amino bonded silica column

USDA-ARS?s Scientific Manuscript database

Effects of mobile phase variations on the chromatographic separation on amino bonded silica column in hydrophilic interaction chromatography (HILIC) were investigated for four zwitterionic tetracyclines (TCs): oxytetracycline, doxycycline, chlortetracycline and tetracycline. A mixed-mode retention m...

[A fatal case series of Rocky Mountain spotted fever in Sonora, México].

PubMed

Delgado-De la Mora, Jesús; Licona-Enríquez, Jesús David; Leyva-Gastélum, Marcia; Delgado-De la Mora, David; Rascón-Alcantar, Adela; Álvarez-Hernández, Gerardo

2018-03-15

Rocky Mountain spotted fever is a highly lethal infectious disease, particularly if specific treatment with doxycycline is given belatedly. To describe the clinical profile of fatal Rocky Mountain spotted fever cases in hospitalized patients in the state of Sonora, México. We conducted a cross-sectional study on a series of 47 deaths caused by Rickettsia rickettsii from 2013 to 2016. The diagnosis of Rocky Mountain spotted fever was confirmed in a single blood sample by polymerase chain reaction (PCR) or by a four-fold increase in immunoglobulin G measured in paired samples analyzed by indirect immunofluorescence. Clinical and laboratory characteristics were compared stratifying subjects into two groups: pediatric and adult. There were no differences in clinical characteristics between groups; petechial rash was the most frequent sign (96%), followed by headache (70%) and myalgia (67%). Although that doxycycline was administered before the fifth day from the onset of symptoms, death occurred in 55% of patients. In clinical laboratory, thrombocytopenia, and biomarkers of liver acute failure and acute kidney failure were the most frequent. Rocky Mountain spotted fever remains as one of the most lethal infectious diseases, which may be related not only to the lack of diagnostic suspicion and delayed administration of doxycycline, but to genotypic characteristics of Rickettsia rickettsii that may play a role in the variability of the fatality rate that has been reported in other geographical regions where the disease is endemic.

Prevalence and Antimicrobial Resistance of Thermophilic Campylobacter spp. from Cattle Farms in Washington State

PubMed Central

Bae, Wonki; Kaya, Katherine N.; Hancock, Dale D.; Call, Douglas R.; Park, Yong Ho; Besser, Thomas E.

2005-01-01

The prevalence of thermophilic Campylobacter spp. was investigated in cattle on Washington State farms. A total of 350 thermophilic Campylobacter isolates were isolated from 686 cattle sampled on 15 farms (eight dairies, two calf rearer farms, two feedlots, and three beef cow-calf ranches). Isolate species were identified with a combination of phenotypic tests, hipO colony blot hybridization, and multiplex lpxA PCR. Breakpoint resistance to four antimicrobials (ciprofloxacin, nalidixic acid, erythromycin, and doxycycline) was determined by agar dilution. Campylobacter jejuni was the most frequent species isolated (34.1%), followed by Campylobacter coli (7.7%) and other thermophilic campylobacters (1.5%). The most frequently detected resistance was to doxycycline (42.3% of 350 isolates). Isolates from calf rearer facilities were more frequently doxycycline resistant than isolates from other farm types. C. jejuni was most frequently susceptible to all four of the antimicrobial drugs studied (58.8% of 272 isolates). C. coli isolates were more frequently resistant than C. jejuni, including resistance to quinolone antimicrobials (89.3% of isolates obtained from calves on calf rearer farms) and to erythromycin (72.2% of isolates obtained from feedlot cattle). Multiple drug resistance was more frequent in C. coli (51.5%) than in C. jejuni (5.1%). The results of this study demonstrate that C. jejuni is widely distributed among Washington cattle farms, while C. coli is more narrowly distributed but significantly more resistant. PMID:15640184

Occurrence of veterinary antibiotics and progesterone in broiler manure and agricultural soil in Malaysia.

PubMed

Ho, Yu Bin; Zakaria, Mohamad Pauzi; Latif, Puziah Abdul; Saari, Nazamid

2014-08-01

Repeated applications of animal manure as fertilizer are normal agricultural practices that may release veterinary antibiotics and hormones into the environment from treated animals. Broiler manure samples and their respective manure-amended agricultural soil samples were collected in selected locations in the states of Selangor, Negeri Sembilan and Melaka in Malaysia to identify and quantify veterinary antibiotic and hormone residues in the environment. The samples were analyzed using ultrasonic extraction followed by solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The broiler manure samples were found to be contaminated with at least six target analytes, namely, doxycycline, enrofloxacin, flumequine, norfloxacin, trimethoprim and tylosin. These analytes were detected in broiler manure samples with maximum concentrations reaching up to 78,516 μg kg(-1) dry weight (DW) (doxycycline). For manure-amended agricultural soil samples, doxycycline and enrofloxacin residues were detected in every soil sample. The maximum concentration of antibiotic detected in soil was 1331 μg kg(-1) DW (flumequine). The occurrence of antibiotics and hormones in animal manure at high concentration poses a risk of contaminating agricultural soil via fertilization with animal manure. Some physico-chemical parameters such as pH, total organic carbon (TOC) and metal content played a considerable role in the fate of the target veterinary antibiotics and progesterone in the environment. It was suggested that these parameters can affect the adsorption of pharmaceuticals to solid environmental matrices. Copyright © 2014 Elsevier B.V. All rights reserved.

Susceptibility to antimicrobial agents of Streptococcus suis capsular type 2 strains isolated from pigs.

PubMed

Seol, B; Kelneric, Z; Hajsig, D; Madic, J; Naglic, T

1996-03-01

The minimal inhibitory concentrations (MICs) for thirty-three epidemiologicaly unrelated clinical isolates of Streptococcus suis capsular type 2 were determined in relation to ampicillin, ampicillin-sulbactam, amoxicillin, clavulanate-amoxicillin, penicillin G, cephalexin, gentamicin, streptomycin, erythromycin, tylosin and doxycycline, using the microtitre broth dilution procedure described by the U.S. National Committee for Clinical Laboratory Standards (NCCLS). Gentamicin was the most active compound tested, with an MIC for 90% of the strains tested (MIC(90)) of 0.4 mg/L. Overall, 70% of strains were resistant to doxycycline (MIC(90) > or = 100.0 mg/L), followed by penicillin G (51% of strains) (MIC(90) + or = 100.0 mg/L). Resistance to amoxicillin and ampicillin was 36.4% (MIC(90) 12.5 mg/L) and 33.3% (MIC(90) 50.0 mg/L), respectively. 15.2% of S. suis strains were resistant to streptomycin, tylosin and cephalexin with MIC90 values of 25.0 mg/L, 12.5 mg/L and 25.0 mg/L, respectively. A combination of ampicillin and sulbactam (MIC(90) 6.3 mg/L) and a combination of amoxicillin and clavulanate (MIC(90) 3.1 mg/L) as well as erythromycin (1.6 mg/L) were of the same efficacy, with a total of 9.1% resistant S. suis strains. This high percentage of resistance to doxycycline and penicillin G precludes the use of these antibiotics as empiric therapy of swine diseases.

The unconstrained evolution of fast and efficient antibiotic-resistant bacterial genomes.

PubMed

Reding-Roman, Carlos; Hewlett, Mark; Duxbury, Sarah; Gori, Fabio; Gudelj, Ivana; Beardmore, Robert

2017-01-30

Evolutionary trajectories are constrained by trade-offs when mutations that benefit one life history trait incur fitness costs in other traits. As resistance to tetracycline antibiotics by increased efflux can be associated with an increase in length of the Escherichia coli chromosome of 10% or more, we sought costs of resistance associated with doxycycline. However, it was difficult to identify any because the growth rate (r), carrying capacity (K) and drug efflux rate of E. coli increased during evolutionary experiments where the species was exposed to doxycycline. Moreover, these improvements remained following drug withdrawal. We sought mechanisms for this seemingly unconstrained adaptation, particularly as these traits ought to trade-off according to rK selection theory. Using prokaryote and eukaryote microorganisms, including clinical pathogens, we show that r and K can trade-off, but need not, because of 'rK trade-ups'. r and K trade-off only in sufficiently carbon-rich environments where growth is inefficient. We then used E. coli ribosomal RNA (rRNA) knockouts to determine specific mutations, namely changes in rRNA operon (rrn) copy number, than can simultaneously maximize r and K. The optimal genome has fewer operons, and therefore fewer functional ribosomes, than the ancestral strain. It is, therefore, unsurprising for r-adaptation in the presence of a ribosome-inhibiting antibiotic, doxycycline, to also increase population size. We found two costs for this improvement: an elongated lag phase and the loss of stress protection genes.

Why sulfonamides are contraindicated in Rocky Mountain spotted fever.

PubMed

Ren, Vicky; Hsu, Sylvia

2014-02-18

Sulfonamide antibiotics are not effective for the treatment of Rocky Mountain spotted fever (RMSF). Patients suspected of having RMSF based on history and physical exam should be treated with doxycycline and not a sulfonamide to avoid increased morbidity and mortality.

[Rocky Mountain spotted fever in Mexican children: Clinical and mortality factors].

PubMed

Álvarez-Hernández, Gerardo; Candia-Plata, María Del Carmen; Delgado-de la Mora, Jesús; Acuña-Meléndrez, Natalia Haydeé; Vargas-Ortega, Anabel Patricia; Licona-Enríquez, Jesús David

2016-06-01

Characterize clinical manifestations and predictors of mortality in children hospitalized for spotted fever. Cross-sectional study in 210 subjects with a diagnosis of Rocky Mountain spotted fever (RMSF) in a pediatric hospital in Sonora, from January 1st, 2004 to June 30th, 2015. Data were analyzed using descriptive statistics and multivariate logistic regression. An upward trend was observed in RMSF morbidity and mortality. Fatality rate was 30%.Three predictors were associated with risk of death: delay ≥ 5 days at the start of doxycycline (ORa= 2.95, 95% CI 1.10-7.95), acute renal failure ((ORa= 8.79, 95% CI 3.46-22.33) and severe sepsis (ORa= 3.71, 95% CI 1.44-9.58). RMSF causes high mortality in children, which can be avoided with timely initiation of doxycycline. Acute renal failure and severe sepsis are two independent predictors of death in children with RMSF.

Tiamulin resistance in porcine Brachyspira pilosicoli isolates.

PubMed

Pringle, M; Landén, A; Franklin, A

2006-02-01

There are few studies on antimicrobial susceptibility of Brachyspira pilosicoli, therefore this study was performed to investigate the situation among isolates from pigs. The tiamulin and tylosin susceptibility was determined by broth dilution for 93 and 86 porcine B. pilosicoli isolates, respectively. The isolates came from clinical samples taken in Swedish pig herds during the years 2002 and 2003. The tylosin minimal inhibitory concentration (MIC) was >16 microg/ml for 50% (n=43) of the isolates tested. A tiamulin MIC >2 microg/ml was obtained for 14% (n=13) of the isolates and these were also tested against doxycycline, salinomycin, valnemulin, lincomycin and aivlosin. For these isolates the susceptibility to salinomycin and doxycycline was high but the MICs for aivlosin varied. The relationship between the 13 tiamulin resistant isolates was analyzed by pulsed-field gel electrophoresis (PFGE). Among the 13 isolates 10 different PFGE patterns were identified.

Imaging and review of a large pre-auricular pilomatrixoma in a child.

PubMed

Whittemore, Kenneth R; Cohen, Michael

2012-05-28

A 10-year-old girl presented with a mildly tender mass in the right preauricular region. The mass became larger, and the overlying skin turned purple. There was no clinical response to a course of either cephalexin or clarithromycin. The remainder of the head and neck examination was normal including normal facial nerve function. Lyme titers and a computed tomographic (CT) scan with contrast of the facial region were obtained. The CT scan demonstrated the lesion to be superficial to the parotid gland. The lyme titer was elevated and doxycycline was begun. The mass appeared to reduce in size after doxycycline treatment, but then grew and turned erythematous. The lesion was surgically excised and was vascular with calcification and cheesy inclusions. The mass was quite close to the skin and the clinical diagnosis at the time of surgery was a pilomatrixoma, which was corroborated on pathological evaluation.

Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

PubMed Central

2012-01-01

Background Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs), for 6 months in rodent models restores insulin receptor function and insulin sensitivity. Methods This 12-week double-blind, randomized, placebo (PL)-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI), doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2). The study included non-DM2 controls (n = 15), and DM2 subjects randomized to PL (n = 13) or doxycycline 100 mg twice daily (MMPI; n = 11). All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment. Results There was a significant decrease in inflammatory markers C-reactive protein (P < 0.05) and myeloperoxidase (P = 0.01) in the MMPI but not PL group. The MMPI also significantly increased skeletal muscle activated/total insulin signaling mediators: 3’phosphoinositide kinase-1 (PDK1) (p < 0.03), protein kinase B (PKB/Akt) (p < 0.004), and glycogen synthase kinase 3ß (GSK3ß) (p < 0.03). Conclusions This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes. Trial Registration Clinicaltrials.gov NCT01375491 PMID:23025537

Changes in Inflammatory and Bone Turnover Markers After Periodontal Disease Treatment in Patients With Diabetes.

PubMed

Izuora, Kenneth E; Ezeanolue, Echezona E; Neubauer, Michael F; Gewelber, Civon L; Allenback, Gayle L; Shan, Guogen; Umpierrez, Guillermo E

2016-06-01

The underlying mechanisms for increased osteopenia and fracture rates in patients with diabetes are not well understood, but may relate to chronic systemic inflammation. We assessed the effect of treating periodontal disease (POD), a cause of chronic inflammation, on inflammatory and bone turnover markers in patients with diabetes. Using an investigator-administered questionnaire, we screened a cross-section of patients presenting for routine outpatient diabetes care. We recruited 22 subjects with POD. Inflammatory and bone turnover markers were measured at baseline and 3 months following POD treatment (scaling, root planing and subantimicrobial dose doxycycline). There were nonsignificant reductions in high-sensitivity C-reactive protein (6.34-5.52mg/L, P = 0.626) and tumor necrosis factor-alpha (10.37-10.01pg/mL, P = 0.617). There were nonsignificant increases in urinary C-terminal telopeptide (85.50-90.23pg/mL, P = 0.684) and bone-specific alkaline phosphatase (7.45-8.79pg/mL, P = 0.074). Patients with >90% adherence with doxycycline were 6.4 times more likely to experience reduction in tumor necrosis factor-alpha (P = 0.021) and 2.8 times more likely to experience reductions in high-sensitivity C-reactive protein (P = 0.133). Treatment of POD in patients with diabetes resulted in nonsignificant lowering of inflammatory markers and nonsignificant increase in bone turnover markers. However, adherence to doxycycline therapy resulted in better treatment effects. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

A study of muscle involvement in scrub typhus.

PubMed

Kalita, Jayantee; Misra, Usha K; Mani, Vinita E; Mahadevan, Anita; Shankar, Susrala K

2015-01-15

Patients with scrub typhus often complain of myalgia, but a comprehensive study on muscle dysfunction is lacking. We therefore report the clinical, electromyographic and muscle biopsy findings in patients with scrub typhus. Consecutive patients with scrub typhus were included, and their clinical and laboratory findings were noted. The patients with myalgia or weakness and elevated serum creatine kinase (CK) were considered to have muscle involvement. Electromyography (EMG) and muscle biopsy were done in some patients. Patients were treated with doxycycline 200mg daily for 7 days, and their clinical and biochemical outcome on discharge and one month were evaluated. 13 out of 33 (39.4%) patients had muscle involvement and their CK levels ranged between 287 and 3166 (859 ± 829) U/L. EMG revealed short duration polyphasic potentials, and muscle histopathology revealed evidence of vasculitis. There were significant correlations between severity of weakness and CK levels (r = -0.6; p < 0.001), platelet counts (r = 0.4; p = 0.04), duration of illness (r = -0.4; p = 0.01) and disability on discharge (r = -0.4; p = 0.04). Patients with muscle involvement had more severe illness evidenced by a lower Glasgow Coma Scale score (p < 0.001), thrombocytopenia (p = 0.05) and greater disability on discharge (p = 0.007), when compared to those without muscle involvement. All the patients had complete recovery following doxycycline therapy, and CK levels also normalized. Muscle dysfunction was present in 39% patients with scrub typhus. Although muscle histopathology showed evidence of vasculitis, patients responded to doxycycline. Copyright © 2014 Elsevier B.V. All rights reserved.

Hydroxychloroquine susceptibility determination of Coxiella burnetii in human embryonic lung (HEL) fibroblast cells.

PubMed

Angelakis, Emmanouil; Khalil, Jacques Bou; Le Bideau, Marion; Perreal, Celine; La Scola, Bernard; Raoult, Didier

2017-07-01

Coxiella burnetii, the causative agent of Q fever, survives and replicates in the acidic environment of monocytes/macrophages; hydroxychloroquine, through alkalinisation of the acidic vacuoles, is critical for the management of Q fever. In this study, a collection of C. burnetii strains isolated from human samples was tested to evaluate the in vitro minimum inhibitory concentrations (MICs) of doxycycline and hydroxychloroquine. Serial two-fold dilutions of doxycycline (0.25-8 mg/L) and hydroxychloroquine (0.25-4 mg/L) were added to C. burnetii-infected human embryonic lung (HEL) fibroblast cells after 48 h of incubation, in duplicate. DNA was detected by C. burnetii-specific semi-quantitative PCR with primers and probes designed for amplification of the IS1111 and IS30A spacers. A total of 29 C. burnetii isolates obtained from 29 patients were tested. Doxycycline MICs ranged from 0.25 mg/L to 0.5 mg/L and hydroxychloroquine MICs from 0.25 mg/L to >4 mg/L. Four C. burnetii stains had hydroxychloroquine MICs ≤ 1 mg/L. The concentration of hydroxychloroquine was associated with a significant decrease in C. burnetii DNA copies in HEL cells based on linear regression analysis (P= 0.01). Recommended serum concentrations of hydroxychloroquine significantly reduced the growth of C. burnetii. Moreover, some C. burnetii strains presented hydroxychloroquine MICs below the recommended serum concentrations, indicating that, for these cases, hydroxychloroquine treatment alone may even be effective. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Determinants of Adherence with Malaria Chemoprophylactic Drugs Used in a Traveler's Health Clinic

PubMed Central

Shady, Ibrahim

2015-01-01

Background. The WHO recommends mefloquine, atovaquone/proguanil, and doxycycline for malaria chemoprophylaxis. Adherence to a drug is determined by many factors. Objective. To detect the determinants of travelers' adherence to malaria chemoprophylaxis. Methods. A prospective comparative study was conducted from January 2012 to July 2013 that included travelers (928 travelers) to malaria endemic countries who visited the THC. They were classified into 3 groups: the 1st is the mefloquine group (396 travelers), the 2nd is the doxycycline group (370 travelers), and finally those who did not receive any drugs (162 travelers). The participants from the 1st and 2nd groups enrolled in the study. Results. Univariate and multivariate analyses were performed. The predictors for adherence in the mefloquine group were travel to an African destination [OR = 51 (6.8–2385)], higher than a secondary school education [OR = 21 (4.1–144.2)], organized travel [OR = 4 (2.1–6.5)], traveling for leisure [OR = 2.1 (1.1–0.4)], and nationality [OR = 2 (1.11–4.00)]. In the doxycycline group, the predictors included higher than a secondary education [OR = 20.1 (4.5–125.1)], organized travel [OR = 11.4 (5.5–20.9)], travel for leisure [OR = 7 (2.3–22.9)], travel to an African destination [OR = 6.1 (0.41–417)], and nationality [OR = 4.5 (2.3–9.5)]. Conclusion. Adherence with malaria chemoprophylaxis could be affected by many factors such as nationality, education, and organized travel. PMID:26379712

The complexity of minocycline serum protein binding.

PubMed

Zhou, Jian; Tran, Brian T; Tam, Vincent H

2017-06-01

Serum protein binding is critical for understanding the pharmacology of antimicrobial agents. Tigecycline and eravacycline were previously reported to have atypical non-linear protein binding; the percentage of free fraction decreased with increasing total concentration. In this study, we extended the investigation to other tetracyclines and examined the factors that might impact protein binding. Different minocycline concentrations (0.5-50 mg/L) and perfusion media (saline, 0.1 M HEPES buffer and 0.1 and 1 M PBS) were examined by in vitro microdialysis. After equilibration, two dialysate samples were taken from each experiment and the respective antimicrobial agent concentrations were analysed by validated LC-MS/MS methods. For comparison, the serum protein bindings of doxycycline and levofloxacin were also determined. The free fraction of minocycline decreased with increasing total concentration, and the results depended on the perfusion media used. The trends of minocycline protein binding in mouse and human sera were similar. In addition, serum protein binding of doxycycline showed the same concentration-dependent trend as minocycline, while the results of levofloxacin were concentration independent. The serum protein bindings of minocycline and doxycycline are negatively correlated with their total concentrations. It is possible that all tetracyclines share the same pharmacological property. Moreover, the specific perfusion media used could also impact the results of microdialysis. Additional studies are warranted to understand the mechanism(s) and clinical implications of serum protein binding of tetracyclines. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline▿

PubMed Central

Briolant, Sébastien; Baragatti, Meili; Parola, Philippe; Simon, Fabrice; Tall, Adama; Sokhna, Cheikh; Hovette, Philippe; Mamfoumbi, Modeste Mabika; Koeck, Jean-Louis; Delmont, Jean; Spiegel, André; Castello, Jacky; Gardair, Jean Pierre; Trape, Jean Francois; Kombila, Maryvonne; Minodier, Philippe; Fusai, Thierry; Rogier, Christophe; Pradines, Bruno

2009-01-01

The distribution and range of 50% inhibitory concentrations (IC50s) of doxycycline were determined for 747 isolates obtained between 1997 and 2006 from patients living in Senegal, Republic of the Congo, and Gabon and patients hospitalized in France for imported malaria. The statistical analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to doxycycline. A triple normal distribution was fitted to the data using a Bayesian mixture modeling approach. The IC50 geometric mean ranged from 6.2 μM to 11.1 μM according to the geographical origin, with a mean of 9.3 μM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC50 mean of 4.9 μM (±2.1 μM [standard deviation]); component B, with an IC50 mean of 7.7 μM (±1.2 μM); and component C, with an IC50 mean of 17.9 μM (±1.4 μM). According to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 μM. PMID:19047651

Rocky Mountain spotted fever in dogs, Brazil.

PubMed

Labruna, Marcelo B; Kamakura, Orson; Moraes-Filho, Jonas; Horta, Mauricio C; Pacheco, Richard C

2009-03-01

Clinical illness caused by Rickettsia rickettsii in dogs has been reported solely in the United States. We report 2 natural clinical cases of Rocky Mountain spotted fever in dogs in Brazil. Each case was confirmed by seroconversion and molecular analysis and resolved after doxycycline therapy.

Role of MAPK Activation in Prostate Cancer Development and Progression

DTIC Science & Technology

2008-03-01

marked by blue highlight). As in human patients, these large lesions caused bladder outlet obstruction and hydronephrosis – distention of the kidney...doxycycline (red outline; note heterogeneous signals within the lesion). Panel c is a representative MR image of hydronephrosis detected in an iBRAF

Rocky Mountain Spotted Fever in Dogs, Brazil

PubMed Central

Kamakura, Orson; Moraes-Filho, Jonas; Horta, Mauricio C.; Pacheco, Richard C.

2009-01-01

Clinical illness caused by Rickettsia rickettsii in dogs has been reported solely in the United States. We report 2 natural clinical cases of Rocky Mountain spotted fever in dogs in Brazil. Each case was confirmed by seroconversion and molecular analysis and resolved after doxycycline therapy. PMID:19239764

Outbreak of Vibrio cholerae serogroup O1, serotype Ogawa, biotype El Tor strain--La Huasteca Region, Mexico, 2013.

PubMed

Díaz-Quiñonez, Alberto; Hernández-Monroy, Irma; Montes-Colima, Norma; Moreno-Pérez, Asunción; Galicia-Nicolás, Adriana; Martínez-Rojano, Hugo; Carmona-Ramos, Concepción; Sánchez-Mendoza, Miroslava; Rodríguez-Martínez, José Cruz; Suárez-Idueta, Lorena; Jiménez-Corona, María Eugenia; Ruiz-Matus, Cuitláhuac; Kuri-Morales, Pablo

2014-06-27

On September 2 and 6, 2013, Mexico's National System of Epidemiological Surveillance identified two cases of cholera in Mexico City. Rectal swab cultures from both patients were confirmed as toxigenic Vibrio cholerae serogroup O1, serotype Ogawa, biotype El Tor. Pulsed-field gel electrophoresis and virulence gene amplification (ctxA, ctxB, zot, and ace) demonstrated that the strains were identical to one another but different from strains circulating in Mexico previously. The strains were indistinguishable from the strain that has caused outbreaks in Haiti, the Dominican Republic, and Cuba. The strain was susceptible to doxycycline, had intermediate susceptibility to ampicillin and chloramphenicol, was less than fully susceptible to ciprofloxacin, and was resistant to furazolidone and trimethoprim-sulfamethoxazole. An investigation failed to identify a common source of infection, additional cases, or any epidemiologic link between the cases. Both patients were treated with a single, 300-mg dose of doxycycline, and their symptoms resolved.

Influence of Mycotoxins and a Mycotoxin Adsorbing Agent on the Oral Bioavailability of Commonly Used Antibiotics in Pigs

PubMed Central

Goossens, Joline; Vandenbroucke, Virginie; Pasmans, Frank; De Baere, Siegrid; Devreese, Mathias; Osselaere, Ann; Verbrugghe, Elin; Haesebrouck, Freddy; De Saeger, Sarah; Eeckhout, Mia; Audenaert, Kris; Haesaert, Geert; De Backer, Patrick; Croubels, Siska

2012-01-01

It is recognized that mycotoxins can cause a variety of adverse health effects in animals, including altered gastrointestinal barrier function. It is the aim of the present study to determine whether mycotoxin-contaminated diets can alter the oral bioavailability of the antibiotics doxycycline and paromomycin in pigs, and whether a mycotoxin adsorbing agent included into diets interacts with those antibiotics. Experiments were conducted with pigs utilizing diets that contained blank feed, mycotoxin-contaminated feed (T-2 toxin or deoxynivalenol), mycotoxin-contaminated feed supplemented with a glucomannan mycotoxin binder, or blank feed supplemented with mycotoxin binder. Diets with T-2 toxin and binder or deoxynivalenol and binder induced increased plasma concentrations of doxycycline administered as single bolus in pigs compared to diets containing blank feed. These results suggest that complex interactions may occur between mycotoxins, mycotoxin binders, and antibiotics which could alter antibiotic bioavailability. This could have consequences for animal toxicity, withdrawal time for oral antibiotics, or public health. PMID:22606377

Fourier transform infrared and Raman spectroscopy studies on magnetite/Ag/antibiotic nanocomposites

NASA Astrophysics Data System (ADS)

Ivashchenko, Olena; Jurga-Stopa, Justyna; Coy, Emerson; Peplinska, Barbara; Pietralik, Zuzanna; Jurga, Stefan

2016-02-01

This article presents a study on the detection of antibiotics in magnetite/Ag/antibiotic nanocomposites using Fourier transform infrared (FTIR) and Raman spectroscopy. Antibiotics with different spectra of antimicrobial activities, including rifampicin, doxycycline, cefotaxime, and ceftriaxone, were studied. Mechanical mixtures of antibiotics and magnetite/Ag nanocomposites, as well as antibiotics and magnetite nanopowder, were investigated in order to identify the origin of FTIR bands. FTIR spectroscopy was found to be an appropriate technique for this task. The spectra of the magnetite/Ag/antibiotic nanocomposites exhibited very weak (for doxycycline, cefotaxime, and ceftriaxone) or even no (for rifampicin) antibiotic bands. This FTIR "invisibility" of antibiotics is ascribed to their adsorbed state. FTIR and Raman measurements show altered Csbnd O, Cdbnd O, and Csbnd S bonds, indicating adsorption of the antibiotic molecules on the magnetite/Ag nanocomposite structure. In addition, a potential mechanism through which antibiotic molecules interact with magnetite/Ag nanoparticle surfaces is proposed.

The application of the micronucleus test in Chinese hamster V79 cells to detect drug-induced photogenotoxicity.

PubMed

Kersten, B; Zhang, J; Brendler-Schwaab, S Y; Kasper, P; Müller, L

1999-09-15

Recent reports on the photochemical carcinogenicity and photochemical genotoxicity of fluoroquinolone antibacterials led to an increasing awareness for the need of a standard approach to test for photochemical genotoxicity. In this study the micronucleus test using V79 cells was adapted to photogenotoxicity testing. Results of using different UVA/UVB relationships enabled us to identify a suitable irradiation regimen for the activation of different kinds of photosensitizers. Using this regimen, 8-methoxypsoralen and the fluoroquinolones lomefloxacin, grepafloxacin and Bay Y 3118 were identified to cause micronuclei and toxicity upon photochemical activation. Among the phenothiazines tested, chlorpromazine and 2-chlorophenothiazine, were positive for both endpoints, whereas triflupromazine was only slightly photoclastogenic in the presence of strong phototoxicity. Among the other potential human photosensitizers tested (oxytetracycline, doxycycline, metronidazole, emodin, hypericin, griseofulvin), only hypericin was slightly photogenotoxic. Photochemical toxicity in the absence of photochemical genotoxicity was noted for doxycycline and emodin. With the assay system described, it is possible to determine photochemical toxicity and photochemical genotoxicity concomitantly with sufficient reliability.

Efficient, footprint-free human iPSC genome editing by consolidation of Cas9/CRISPR and piggyBac technologies.

PubMed

Wang, Gang; Yang, Luhan; Grishin, Dennis; Rios, Xavier; Ye, Lillian Y; Hu, Yong; Li, Kai; Zhang, Donghui; Church, George M; Pu, William T

2017-01-01

Genome editing of human induced pluripotent stem cells (hiPSCs) offers unprecedented opportunities for in vitro disease modeling and personalized cell replacement therapy. The introduction of Cas9-directed genome editing has expanded adoption of this approach. However, marker-free genome editing using standard protocols remains inefficient, yielding desired targeted alleles at a rate of ∼1-5%. We developed a protocol based on a doxycycline-inducible Cas9 transgene carried on a piggyBac transposon to enable robust and highly efficient Cas9-directed genome editing, so that a parental line can be expeditiously engineered to harbor many separate mutations. Treatment with doxycycline and transfection with guide RNA (gRNA), donor DNA and piggyBac transposase resulted in efficient, targeted genome editing and concurrent scarless transgene excision. Using this approach, in 7 weeks it is possible to efficiently obtain genome-edited clones with minimal off-target mutagenesis and with indel mutation frequencies of 40-50% and homology-directed repair (HDR) frequencies of 10-20%.

Ureaplasma parvum causing life-threatening disease in a susceptible patient.

PubMed

Korytny, Alexander; Nasser, Roni; Geffen, Yuval; Friedman, Tom; Paul, Mical; Ghanem-Zoubi, Nesrin

2017-08-16

A 56-year-old man with lymphoma developed orchitis followed by septic arthritis of his right glenohumeral joint. Synovial fluid cultures were negative but PCR amplification test was positive for Ureaplasmaparvum. The patient was treated with doxycycline. Two and a half years later, the patient presented with shortness of breath and grade III/IV diastolic murmur on auscultation. Echocardiography revealed severely dilated left heart chambers, severe aortic regurgitation and several mobile masses on the aortic valve cusps suspected to be vegetations. He underwent valve replacement; valve tissue culture was negative but the 16S rRNA gene amplification test was positive for U. parvum He was treated again with doxycycline. In an outpatient follow-up 1 year and 3 months later, the patient was doing well. Repeated echocardiography showed normal aortic prosthesis function. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Treatment of Tularemia in Patient with Chronic Graft-versus-Host Disease

PubMed Central

Seibold, Erik; Knabbe, Cornelius; Kaufmann, Martin; Splettstoesser, Wolf

2013-01-01

We describe a case of human tularemia caused by Francisella tularensis subsp. holarctica in a stem cell transplant recipient with chronic graft-versus-host disease who was receiving levofloxacin prophylaxis. The infection was characterized by pneumonia with septic complications. The patient was successfully treated with doxycycline. PMID:23647853

Synergistic activity of antibiotics combined with ivermectin to kill body lice.

PubMed

Sangaré, Abdoul Karim; Rolain, Jean Marc; Gaudart, Jean; Weber, Pascal; Raoult, Didier

2016-03-01

Ivermectin and doxycycline have been found to be independently effective in killing body lice. In this study, 450 body lice were artificially fed on a Parafilm™ membrane with human blood associated with antibiotics (doxycycline, erythromycin, rifampicin and azithromycin) alone and in combination with ivermectin. Fluorescence in situ hybridisation and spectral deconvolution were performed to evaluate bacterial transcriptional activity following antibiotic intake by the lice. In the first series, a lethal effect of antibiotics on lice was observed compared with the control group at 18 days (log-rank test, P≤10(-3)), with a significant difference between groups in the production of nits (P=0.019, Kruskal-Wallis test). A high lethal effect of ivermectin alone (50ng/mL) was observed compared with the control group (log-rank test, P≤10(-3)). Fluorescence of bacteriocytes in lice treated with 20μg/mL doxycycline was lower than in untreated lice (P<0.0001, Kruskal-Wallis test). In the second series with antibiotic-ivermectin combinations, a synergistic lethal effect on treated lice (log-rank test, P<10(-6)) was observed compared with the control group at 18 days, associated with a significant decrease in the production of nits (P≤0.001, Kruskal-Wallis test). Additionally, survival of lice in the combination treatment groups compared with ivermectin alone was significant (log-rank test, P=0.0008). These data demonstrate that the synergistic effect of combinations of antibiotics and ivermectin could be used to achieve complete eradication of lice and to avoid selection of a resistant louse population. Copyright © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Diabetes Mellitus in Pregnancy Leads to Growth Restriction and Epigenetic Modification of the Srebf2 Gene in Rat Fetuses.

PubMed

Golic, Michaela; Stojanovska, Violeta; Bendix, Ivo; Wehner, Anika; Herse, Florian; Haase, Nadine; Kräker, Kristin; Fischer, Caroline; Alenina, Natalia; Bader, Michael; Schütte, Till; Schuchardt, Mirjam; van der Giet, Markus; Henrich, Wolfgang; Muller, Dominik N; Felderhoff-Müser, Ursula; Scherjon, Sicco; Plösch, Torsten; Dechend, Ralf

2018-05-01

Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health. © 2018 American Heart Association, Inc.

In vitro evaluation of antibiotic synergy for polymyxin B-resistant carbapenemase-producing Klebsiella pneumoniae.

PubMed

Elemam, Azza; Rahimian, Joseph; Doymaz, Mehmet

2010-10-01

Since carbapenemase-producing Klebsiella pneumoniae strains were first reported in North Carolina, these highly resistant organisms have been isolated with increasing frequency, especially in the New York City area. Polymyxin B is one of the few antimicrobials that retain reliable activity against these organisms. However, polymyxin B MICs are elevated against K. pneumoniae isolates with increasing frequency, leaving clinicians with few therapeutic options. We investigated several antimicrobial agents for potential synergy with polymyxin B against 12 clinical strains of carbapenemase-producing K. pneumoniae. A broth microdilution assay using a 96-well plate was developed in which graded dilutions of polymyxin B and the study drug were incubated with resistant isolates in a checkerboard pattern. Polymyxin B was studied in combination with cefazolin, ceftriaxone, cefepime, imipenem, gentamicin, tigecycline, doxycycline, and rifampin. All K. pneumoniae strains tested positive for K. pneumoniae carbapenemase (KPC) genes by real-time PCR and had elevated polymyxin B MIC values ranging from 16 to 128 μg/ml. Synergy was observed with the combination of polymyxin B and rifampin as well as with polymyxin B and doxycycline, resulting in at least a 4-fold decrease in the polymyxin B MIC. For both combinations, this effect occurred at physiologically achievable concentrations. Less pronounced synergy was noted with tigecycline and polymyxin B. No synergy was observed at physiologic concentrations with the other antimicrobials studied. These results suggest that rifampin, doxycycline, and tigecycline may be useful additions to polymyxin B in the treatment of infections caused by highly resistant carbapenemase-producing K. pneumoniae. Further studies are warranted to determine if these in vitro findings translate into clinical efficacy.

Notch3 as a novel therapeutic target in metastatic medullary thyroid cancer.

PubMed

Lou, Irene; Odorico, Scott; Yu, Xiao-Min; Harrison, April; Jaskula-Sztul, Renata; Chen, Herbert

2018-01-01

Medullary thyroid cancer portends poor survival once liver metastasis occurs. We hypothesize that Notch3 overexpression in medullary thyroid cancer liver metastasis will decrease proliferation and growth of the tumor. TT cells were modified genetically to overexpress Notch3 in the presence of doxycycline, creating the TT-Notch3 cell line. Mice were injected intrasplenically with either TT-Notch3 or control vector TT-TRE cells. Each cell line had 3 treatment groups: control with 12 weeks of standard chow, early DOX with doxycycline chow at day 0 and for 70 days thereafter, and late DOX with doxycycline chow at 8 weeks. Each animal underwent micro-computed tomography to evaluate for tumor formation and tumor quantification was performed. Animals were killed at 12 weeks, and the harvested liver was stained with Ki-67, hematoxylin and eosin, and Notch3. Induction of Notch3 did not prevent formation of medullary thyroid cancer liver metastases as all mice in the early DOX group developed tumors. However, induction of Notch after medullary thyroid cancer liver tumor formation decreased tumor size, as seen on micro-computed tomography scans (late DOX group). This translated to a 37-fold decrease in tumor volume (P = .001). Notch3 overexpression also resulted in decreased Ki-67 index (P = .038). Moreover, Notch3 induction led to increased areas of neutrophil infiltration and necrosis on hematoxylin and eosin staining of the tumors CONCLUSION: Notch3 overexpression demonstrates an antiproliferative effect on established metastatic medullary thyroid cancer liver tumors and is a potential therapeutic target in treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice.

PubMed

Kesby, James P; Markou, Athina; Semenova, Svetlana

2016-10-01

Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT- control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT- mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT- mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT- mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT- mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT- mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Environmental Exposure, Estrogen and Two X Chromosomes are Required for Disease Development in an Epigenetic Model of Lupus

PubMed Central

Strickland, Faith M.; Hewagama, Anura; Lu, Qianjian; Wu, Ailing; Hinderer, Robert; Webb, Ryan; Johnson, Kent; Sawalha, Amr H.; Delaney, Colin; Yung, Raymond; Richardson, Bruce C.

2011-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease primarily afflicting women. The reason for the gender bias is unclear, but genetic susceptibility, estrogen and environmental agents appear to play significant roles in SLE pathogenesis. Environmental agents can contribute to lupus susceptibility through epigenetic mechanisms. We used (C57BL/6 × SJL)F1 mice transgenic for a dominant-negative MEK (dnMEK) that was previously shown to be inducibly and selectively expressed in T cells. In this model, induction of the dnMEK by doxycycline treatment suppresses T cell ERK signaling, decreasing DNA methyltransferase expression and resulting in DNA demethylation, overexpression of immune genes Itgal (CD11a) and Tnfsf7 (CD70), and anti-dsDNA antibody. To examine the role of gender and estrogen in this model, male and female transgenic mice were neutered and implanted with time-release pellets delivering placebo or estrogen. Doxycycline induced IgG anti-dsDNA antibodies in intact and neutered, placebo-treated control female but not male transgenic mice. Glomerular IgG deposits were also found in the kidneys of female but not male transgenic mice, and not in the absence of doxycycline. Estrogen enhanced anti-dsDNA IgG antibodies only in transgenic, ERK-impaired female mice. Decreased ERK activation also resulted in overexpression and demethylation of the X-linked methylation-sensitive gene CD40lg in female but not male mice, consistent with demethylation of the second X chromosome in the females. The results show that both estrogen and female gender contribute to the female predisposition in lupus susceptibility through hormonal and epigenetic X chromosome effects and through suppression of ERK signaling by environmental agents. PMID:22142890

Chlamydia trachomatis in Cervical Lymph Node of Man with Lymphogranuloma Venereum, Croatia, 20141.

PubMed

Gjurašin, Branimir; Lepej, Snježana Židovec; Cole, Michelle J; Pitt, Rachel; Begovac, Josip

2018-04-01

We report an HIV-infected person who was treated for lymphogranuloma venereum cervical lymphadenopathy and proctitis in Croatia in 2014. Infection with a variant L2b genovar of Chlamydia trachomatis was detected in a cervical lymph node aspirate. A prolonged course of doxycycline was required to cure the infection.

Bubonic lymphogranuloma venereum with multidrug treatment failure.

PubMed

Vall-Mayans, Martí; Isaksson, Jenny; Caballero, Estrella; Sallés, Beatriz; Herrmann, Björn

2014-03-01

A patient with proctitis and inguinal buboes diagnosed with lymphogranuloma venereum (LGV) was treated with doxycycline 21 days, azithromycin 20 days and moxifloxacin for a further 12 days because of progressive worsening of inguinal symptoms. Despite extensive antibiotic treatment, the inguinal LGV lesions persisted; however, the patient recovered spontaneously after three months.

Chlamydia trachomatis in Cervical Lymph Node of Man with Lymphogranuloma Venereum, Croatia, 20141

PubMed Central

Lepej, Snježana Židovec; Cole, Michelle J.; Pitt, Rachel; Begovac, Josip

2018-01-01

We report an HIV-infected person who was treated for lymphogranuloma venereum cervical lymphadenopathy and proctitis in Croatia in 2014. Infection with a variant L2b genovar of Chlamydia trachomatis was detected in a cervical lymph node aspirate. A prolonged course of doxycycline was required to cure the infection. PMID:29553338

Diagnosis and Management of Borrelia turicatae Infection in Febrile Soldier, Texas, USA

PubMed Central

Pietralczyk, Elizabeth; Lopez, Job E.; Brooks, Christopher; Schriefer, Martin E.; Wozniak, Edward; Stermole, Benjamin

2017-01-01

In August 2015, a soldier returned from field exercises in Texas, USA, with nonspecific febrile illness. Culture and sequencing of spirochetes from peripheral blood diagnosed Borrelia turicatae infection. The patient recovered after receiving doxycycline. No illness occurred in asymptomatic soldiers potentially exposed to the vector tick and prophylactically given treatment. PMID:28418310

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

PubMed Central

Mishra, Nibha; Milikovsky, Dan Z.; Hanin, Geula; Zelig, Daniel; Sheintuch, Liron; Berson, Amit; Greenberg, David S.; Friedman, Alon

2017-01-01

Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and

Clinical management of Brucella suis infection in dogs and implications for public health.

PubMed

James, D R; Golovsky, G; Thornton, J M; Goodchild, L; Havlicek, M; Martin, P; Krockenberger, M B; Marriott, Dje; Ahuja, V; Malik, R; Mor, S M

2017-01-01

Brucellosis caused by Brucella suis is a notifiable disease that has recently emerged in dogs in New South Wales (NSW). Given the potential for zoonotic transmission, euthanasia of affected dogs is recommended, but this action is not mandatory. We report the clinical management of three dogs that underwent treatment at their owners' request. A 14-month-old spayed female crossbreed originally obtained from an urban animal shelter underwent extensive investigations in 2011-12 for lameness and back pain, culminating in decompressive laminectomy. Diagnosis of multifocal discospondylitis and spinal empyema was made, with B. suis cultured from surgical biopsy specimens. The dog responded to long-term treatment using rifampicin and doxycycline. A second case of B. suis infection was diagnosed in January 2016 in a 3-year-old crossbreed pig-hunting dog with unilateral testicular enlargement. Following serological diagnosis the dog was given preliminary therapy using rifampicin and doxycycline, the affected testis was resected and the patient given a further month of combination therapy. In March 2016 a 7-year-old crossbreed pig-hunting dog with brucellosis was handled similarly, although both testes were removed. Brucellosis should be considered in the differential diagnosis of back pain, discospondylitis, lameness, abortion, prostatic abscessation and testicular/epididymal enlargement in dogs, especially if there is exposure to feral pigs or consumption of uncooked feral pig meat. Euthanasia is the only guarantee of reducing the public health risk to zero. However, where treatment is desired by the owner, combination therapy using rifampicin and doxycycline appears to be effective, when combined with surgical resection of infected tissues. Further monitoring of dogs during and after treatment is required to document cure. © 2017 Australian Veterinary Association.

Chronic skin-specific inflammation promotes vascular inflammation and thrombosis.

PubMed

Wang, Yunmei; Gao, Huiyun; Loyd, Candace M; Fu, Wen; Diaconu, Doina; Liu, Shijian; Cooper, Kevin D; McCormick, Thomas S; Simon, Daniel I; Ward, Nicole L

2012-08-01

Patients with psoriasis have systemic and vascular inflammation and are at increased risk for myocardial infarction, stroke, and cardiovascular death. However, the underlying mechanism(s) mediating the link between psoriasis and vascular disease is incompletely defined. This study sought to determine whether chronic skin-specific inflammation has the capacity to promote vascular inflammation and thrombosis. Using the KC-Tie2 doxycycline-repressible (Dox-off) murine model of psoriasiform skin disease, spontaneous aortic root inflammation was observed in 33% of KC-Tie2 compared with 0% of control mice by 12 months of age (P=0.04) and was characterized by the accumulation of macrophages, T lymphocytes, and B lymphocytes, as well as by reduced collagen content and increased elastin breaks. Importantly, aortic inflammation was preceded by increases in serum tumor necrosis factor-α, IL-17A, vascular endothelial growth factor, IL-12, monocyte chemotactic protein-1, and S100A8/A9, as well as splenic and circulating CD11b(+)Ly-6C(hi) pro-inflammatory monocytes. Doxycycline treatment of old mice with severe skin disease eliminated skin inflammation and the presence of aortic root lesion in 1-year-old KC-Tie2 animals. Given the bidirectional link between inflammation and thrombosis, arterial thrombosis was assessed in KC-Tie2 and control mice; mean time to occlusive thrombus formation was shortened by 64% (P=0.002) in KC-Tie2 animals; and doxycycline treatment returned thrombosis clotting times to that of control mice (P=0.69). These findings demonstrate that sustained skin-specific inflammation promotes aortic root inflammation and thrombosis and suggest that aggressive treatment of skin inflammation may attenuate pro-inflammatory and pro-thrombotic pathways that produce cardiovascular disease in psoriasis patients.

Construction and modelling of an inducible positive feedback loop stably integrated in a mammalian cell-line.

PubMed

Siciliano, Velia; Menolascina, Filippo; Marucci, Lucia; Fracassi, Chiara; Garzilli, Immacolata; Moretti, Maria Nicoletta; di Bernardo, Diego

2011-06-01

Understanding the relationship between topology and dynamics of transcriptional regulatory networks in mammalian cells is essential to elucidate the biology of complex regulatory and signaling pathways. Here, we characterised, via a synthetic biology approach, a transcriptional positive feedback loop (PFL) by generating a clonal population of mammalian cells (CHO) carrying a stable integration of the construct. The PFL network consists of the Tetracycline-controlled transactivator (tTA), whose expression is regulated by a tTA responsive promoter (CMV-TET), thus giving rise to a positive feedback. The same CMV-TET promoter drives also the expression of a destabilised yellow fluorescent protein (d2EYFP), thus the dynamic behaviour can be followed by time-lapse microscopy. The PFL network was compared to an engineered version of the network lacking the positive feedback loop (NOPFL), by expressing the tTA mRNA from a constitutive promoter. Doxycycline was used to repress tTA activation (switch off), and the resulting changes in fluorescence intensity for both the PFL and NOPFL networks were followed for up to 43 h. We observed a striking difference in the dynamics of the PFL and NOPFL networks. Using non-linear dynamical models, able to recapitulate experimental observations, we demonstrated a link between network topology and network dynamics. Namely, transcriptional positive autoregulation can significantly slow down the "switch off" times, as compared to the non-autoregulated system. Doxycycline concentration can modulate the response times of the PFL, whereas the NOPFL always switches off with the same dynamics. Moreover, the PFL can exhibit bistability for a range of Doxycycline concentrations. Since the PFL motif is often found in naturally occurring transcriptional and signaling pathways, we believe our work can be instrumental to characterise their behaviour.

Staphylococcus aureus colonization of healthy military service members in the United States and Afghanistan.

PubMed

Vento, Todd J; Calvano, Tatjana P; Cole, David W; Mende, Katrin; Rini, Elizabeth A; Tully, Charla C; Landrum, Michael L; Zera, Wendy; Guymon, Charles H; Yu, Xin; Beckius, Miriam L; Cheatle, Kristelle A; Murray, Clinton K

2013-07-16

Staphylococcus aureus [methicillin-resistant and methicillin-susceptible (MRSA/MSSA)] is a leading cause of infections in military personnel, but there are limited data regarding baseline colonization of individuals while deployed. We conducted a pilot study to screen non-deployed and deployed healthy military service members for MRSA/MSSA colonization at various anatomic sites and assessed isolates for molecular differences. Colonization point-prevalence of 101 military personnel in the US and 100 in Afghanistan was determined by swabbing 7 anatomic sites. US-based individuals had received no antibiotics within 30 days, and Afghanistan-deployed personnel were taking doxycycline for malaria prophylaxis. Isolates underwent identification and testing for antimicrobial resistance, virulence factors, and pulsed-field type (PFT). 4 individuals in the US (4 isolates- 3 oropharynx, 1 perirectal) and 4 in Afghanistan (6 isolates- 2 oropharynx, 2 nare, 1 hand, 1 foot) were colonized with MRSA. Among US-based personnel, 3 had USA300 (1 PVL+) and 1 USA700. Among Afghanistan-based personnel, 1 had USA300 (PVL+), 1 USA800 and 2 USA1000. MSSA was present in 40 (71 isolates-25 oropharynx, 15 nare) of the US-based and 32 (65 isolates- 16 oropharynx, 24 nare) of the Afghanistan-based individuals. 56 (79%) US and 41(63%) Afghanistan-based individuals had MSSA isolates recovered from extra-nare sites. The most common MSSA PFTs were USA200 (9 isolates) in the US and USA800 (7 isolates) in Afghanistan. MRSA/MSSA isolates were susceptible to doxycycline in all but 3 personnel (1 US, 2 Afghanistan; all were MSSA isolates that carried tetM). MRSA and MSSA colonization of military personnel was not associated with deployment status or doxycycline exposure. Higher S. aureus oropharynx colonization rates were observed and may warrant changes in decolonization practices.

Comparison of bleaching efficacy of two bleaching agents on teeth discoloured by different antibiotic combinations used in revascularization.

PubMed

Yasa, Bilal; Arslan, Hakan; Akcay, Merve; Kavrik, Fevzi; Hatirli, Huseyin; Ozkan, Bulent

2015-07-01

To investigate the whitening effects of different bleaching agents on teeth discoloured by different antibiotic combinations of ciprofloxacin and metronidazole with minocycline, doxycycline, amoxicillin or cefaclor. Forty extracted bovine incisors were collected and discoloured with triple antibiotic pastes (TAP) with minocycline, doxycycline, amoxicillin and cefaclor throughout 30 days. The specimens were then randomly divided into two subgroups and each group received different bleaching materials: 35% hydrogen peroxide and sodium perborate. Spectrophotometric measurements were obtained on the buccal surfaces of the crown, firstly in the beginning, then on the 4th, 8th and 12th days after the placement of the bleaching materials. The acceptability threshold was set to 3.5. The ∆E values were calculated and the data was analysed using the repeated measures analysis of variance (P = .05). All the test groups induced colour changes exceeding the acceptability threshold 30 days after the antibiotic pastes were placed. The 35% hydrogen peroxide was more effective than sodium perborate in the whitening of discoloured teeth by antibiotic pastes (P = .001). The whitening effect after the 8th and 12th days was significantly more than after 4 days of treatment (P <.001). The discolouration caused by the TAP with minocycline and cefaclor showed greater whitening compared to the TAP with doxycycline and amoxicillin groups (P <.05). The whitening treatment effect of 35% hydrogen peroxide on teeth discoloured by antibiotic pastes seems to have significantly outperformed the sodium perborate treatment. Both bleaching agents were allowed to bleach the teeth gradually each day and the effects on the 8th and 12th days were superior to the one on the 4th day. The use of 35% hydrogen peroxide could be advantageous to bleach the teeth discoloured with antibiotic pastes compared to sodium perborate.

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity.

PubMed

Bekenstein, Uriya; Mishra, Nibha; Milikovsky, Dan Z; Hanin, Geula; Zelig, Daniel; Sheintuch, Liron; Berson, Amit; Greenberg, David S; Friedman, Alon; Soreq, Hermona

2017-06-20

Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca 2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and

Staphylococcus aureus colonization of healthy military service members in the United States and Afghanistan

PubMed Central

2013-01-01

Background Staphylococcus aureus [methicillin-resistant and methicillin-susceptible (MRSA/MSSA)] is a leading cause of infections in military personnel, but there are limited data regarding baseline colonization of individuals while deployed. We conducted a pilot study to screen non-deployed and deployed healthy military service members for MRSA/MSSA colonization at various anatomic sites and assessed isolates for molecular differences. Methods Colonization point-prevalence of 101 military personnel in the US and 100 in Afghanistan was determined by swabbing 7 anatomic sites. US-based individuals had received no antibiotics within 30 days, and Afghanistan-deployed personnel were taking doxycycline for malaria prophylaxis. Isolates underwent identification and testing for antimicrobial resistance, virulence factors, and pulsed-field type (PFT). Results 4 individuals in the US (4 isolates- 3 oropharynx, 1 perirectal) and 4 in Afghanistan (6 isolates- 2 oropharynx, 2 nare, 1 hand, 1 foot) were colonized with MRSA. Among US-based personnel, 3 had USA300 (1 PVL+) and 1 USA700. Among Afghanistan-based personnel, 1 had USA300 (PVL+), 1 USA800 and 2 USA1000. MSSA was present in 40 (71 isolates-25 oropharynx, 15 nare) of the US-based and 32 (65 isolates- 16 oropharynx, 24 nare) of the Afghanistan-based individuals. 56 (79%) US and 41(63%) Afghanistan-based individuals had MSSA isolates recovered from extra-nare sites. The most common MSSA PFTs were USA200 (9 isolates) in the US and USA800 (7 isolates) in Afghanistan. MRSA/MSSA isolates were susceptible to doxycycline in all but 3 personnel (1 US, 2 Afghanistan; all were MSSA isolates that carried tetM). Conclusion MRSA and MSSA colonization of military personnel was not associated with deployment status or doxycycline exposure. Higher S. aureus oropharynx colonization rates were observed and may warrant changes in decolonization practices. PMID:24060181

Neovascularization and neoinnervation of subcutaneously placed nucleus pulposus and the inhibitory effects of certain drugs.

PubMed

Olmarker, Kjell

2005-07-01

An experimental study in the pig with autologous transfer of nucleus pulpous and retroperitoneal fat to the subcutaneous space of the back. To evaluate if there is neovascularization or neoinnervation of subcutaneously placed nucleus pulposus, in comparison to retroperitoneal fat, and under simultaneous treatment by certain antiangiogenetic drugs. It has been suggested that intervertebral discs may be invaded by newly formed blood vessels and nerve fibers following injury of the anulus fibrosus. The nerve fibers have been considered to induce low back pain. However, it is still debated whether such ingrowth may occur and, if present, if this is based on the action of angiogenetic substances in the intervertebral disc or simply by normal would healing. In the first series, autologous nucleus pulposus and retroperitoneal fat was placed subcutaneously in 3 pigs. In the second series, autologous nucleus pulposus was placed subcutaneously with simultaneous treatment with methotrexate (n = 3), celecoxib (n = 3), doxycycline (n = 3), and infliximab (n = 3). After 7 days, the tissue was collected and processed immunohistochemically for the visualization of blood vessels and nerve fibers. There was a number of blood vessels and nerve fibers in the nucleus pulposus samples, while no vessels were observed in the fat samples. Neither methotrexate nor celecoxib seemed to be able to reduce the ingrowth of blood vessels (neovascularization) or nerve fibers (neoinnervation). Treatment by doxycycline and infliximab markedly reduced both neovascularization and neoinnervation. Subcutaneously placed autologous nucleus pulposus displays an ingrowth of newly formed blood vessels and nerve fibers within 7 days, in contrast to retroperitoneal fat. Such ingrowth seems to be reduced by doxycycline and infliximab, 2 cytokine inhibitors. The data suggest that the ingrowth may be induced by bioactive substances within the nucleus pulposus. The clinical importance of these data has yet to be

A Phase II Study of Doxycycline in Relapsed NHL

ClinicalTrials.gov

2016-10-27

Adult Diffuse Large B-Cell Lymphoma; Mantle Cell Lymphoma Recurrent; Lymphoma, Follicular; Marginal Zone B-Cell Lymphoma; Malignant Lymphoma - Lymphoplasmacytic; Waldenstrom Macroglobulinemia; Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia (CLL); T-Cell Lymphoma

In vitro antibiotic susceptibility of Mycoplasma iguanae proposed sp. nov. isolated from vertebral lesions of green iguanas (Iguana iguana).

PubMed

Westfall, Megan E; Demcovitz, Dina L; Plourdé, Daisy R; Rotstein, David S; Brown, Daniel R

2006-06-01

Mycoplasma iguanae proposed species nova was isolated from vertebral abscesses of two feral iguanas (Iguana iguana) from Florida. Three strains were evaluated for sensitivity to a variety of antibiotics. The minimum inhibitory concentrations for M. iguanae, assessed by broth dilution methods, of clindamycin, doxycycline, enrofloxacin, oxytetracycline, and tylosin (all <1 microg/ml) were lower than those of chloramphenicol (32 micro/ml) and erythromycin (64 microg/ml). The profile was identical to that of Mycoplasma alligatoris, previously isolated from American alligators (Alligator mississippiensis). M. iguanae strain 2327T was subcultured without antibiotics to assess mycoplasmacidal activity. Clindamycin, doxycycline, oxytetracycline, and tylosin were bacteriostatic from 0.1 to 0.5 microg/ml, whereas enrofloxacin was bactericidal at 20 ng/ml. An enrofloxacin dosage of 5-10 mg/kg achieves peak plasma concentrations >1 microg/ml, with an elimination half-life of 6-20 hr, in alligators. Although concentrations achieved in the vertebrae by i.m. or i.v. injection are probably lower than those in plasma, these data suggest that enrofloxacin may be useful to treat M. iguanae mycoplasmosis in iguanas.

In vitro comparison of the activity of various antibiotics and drugs against new Taiwan isolates and standard strains of avian mycoplasma.

PubMed

Lin, M Y

1987-01-01

Twenty-nine antibiotics or drugs were incorporated individually into mycoplasma agar to evaluate their inhibitory activity against avian mycoplasmas: 100 recent Taiwan isolates of 7 serotypes and 10 standard strains of 7 serotypes were tested. All of the standard strains were very sensitive to erythromycin, chlorotetracycline, doxycycline, minocycline, and tetracycline, but the local isolates were highly resistant to these antibiotics. The drugs or antibiotics that possessed an MIC90 of 50 micrograms/ml or less against the local isolates were tiamulin (less than 0.4 micrograms/ml), lincospectin (2.7), josamycin (2.7), lincomycin (3.0), spectinomycin (4.8), tylosin (6.0), kanamycin (6.0), chloramphenicol (6.0), gentamicin (7.5), apramycin (24.5), doxycycline (27.4), minocycline (29.0), spiramycin (30.0), colistin (44.3), leucomycin (45.0), and streptomycin (50.0). The MIC90 of the other antibiotics or drugs was greater than 50 micrograms/ml. None of the isolates or strains were sensitive to nalidixic acid, ronidazole, penicillin, ampicillin, cephalexin, carbadox, or four sulfa drugs at a concentration about 5 times the therapeutic level.

Pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum: important lessons from a case series.

PubMed

Oud, Emerentiana Veronica; de Vrieze, Nynke Hesselina Neeltje; de Meij, Arjan; de Vries, Henry John C

2014-06-01

Current lymphogranuloma venereum (LGV) guidelines mainly focus on anorectal infections. Inguinal LGV infections have been rare in the current epidemic among men who have sex with men (MSM), but might require a different approach not yet recommended in current guidelines for the treatment and diagnosis of LGV. We describe 4 inguinal LGV cases. Three MSM developed inguinal LGV infection several weeks after a previous consultation, of which two had received azithromycin after being notified for LGV. Three failed the recommended 21 days doxycycline treatment. These inguinal LGV cases highlight 3 pitfalls in the current standard management of LGV: (1) Urethral chlamydia infections in MSM can be caused by LGV biovars that in contrast to non-LGV biovars require prolonged antibiotic therapy. (2) The recommended one gram azithromycin contact treatment seems insufficient to prevent established infections. (3) Inguinal LGV may require prolonged courses of doxycycline, exceeding the currently advised 21 days regimen. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A case of hemifacial paresis in a patient with Lyme neuroborreliosis treated with antibiotics in whom Borrelia meningitis developed.

PubMed

Shimizu, Hisao; Haratani, Koji; Miyazaki, Masayuki; Kakehi, Yoshiaki; Nagami, Shuhei; Katanami, Yuichi; Kawabata, Hiroki; Takahashi, Nobuyuki

2016-07-28

A 38-year-old man visited our hospital because of hemifacial paresis that developed 2 months after being bit by a tick. We diagnosed idiopathic peripheral facial palsy and gave the patient oral prednisolone and valacyclovir. Although the symptoms completely resolved in about 2 weeks, there was a risk of Lyme neuroborreliosis. The patient therefore received doxycycline (100 mg twice daily) and amoxicillin (1,000 mg 3 times daily) for 14 days. Two months later, he had symptoms of meningitis such as headache and fever accompanied by lymphocytic cerebrospinal fluid pleocytosis. Viral meningitis was diagnosed and treated with parenteral acyclovir. The symptoms of meningitis improved. Tests for serum IgG antibodies against borrelia were positive. We gave the patient a diagnosis of Lyme neuroborreliosis. The patient received intravenous ceftriaxone and had no relapse. It is a rare for meningitis to develop in a patient with cranial neuropathy who received doxycycline. Lyme neuroborreliosis is a rare disease in Japan. Care should therefore be exercised in the diagnosis of Lyme neuroborreliosis and evaluation of the response to treatment.

Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action

PubMed Central

Griffin, Michael O.; Ceballos, Guillermo; Villarreal, Francisco

2010-01-01

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The firstt of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline’s multiple mechanisms of action as a means to understand their beneficial effects. PMID:20951211

Rocky Mountain spotted fever in children.

PubMed

Woods, Charles R

2013-04-01

Rocky Mountain spotted fever is typically undifferentiated from many other infections in the first few days of illness. Treatment should not be delayed pending confirmation of infection when Rocky Mountain spotted fever is suspected. Doxycycline is the drug of choice even for infants and children less than 8 years old. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of simultaneous splenic sample PCR with blood sample PCR for diagnosis and treatment of experimental Ehrlichia canis infection.

PubMed

Harrus, Shimon; Kenny, Martin; Miara, Limor; Aizenberg, Itzhak; Waner, Trevor; Shaw, Susan

2004-11-01

This report presents evidence that dogs recover from acute canine monocytic ehrlichiosis (CME) after 16 days of doxycycline treatment (10 mg/kg of body weight every 24 h). Blood PCR was as valuable as splenic aspirate PCR for early diagnosis of acute CME. Splenic aspirate PCR was, however, superior to blood PCR for the evaluation of ehrlichial elimination.

Lymphogranuloma venereum proctitis

PubMed Central

Harrison, Tucker; Stroup, Jeff

2016-01-01

We describe a 60-year-old man who presented with rectal pain and bleeding of a month's duration. His presentation was highly suggestive of lymphogranuloma venereum (LGV) proctitis. Nucleic acid amplification for chlamydia and gonorrhea via rectal swab revealed evidence supportive of anorectal chlamydia. Treatment with doxycycline resulted in complete resolution of his symptoms. PMID:27695183

Batch medication of intestinal infections in nursery pigs-A randomised clinical trial on the efficacy of treatment strategy, type of antibiotic and bacterial load on average daily weight gain.

PubMed

Weber, Nicolai Rosager; Pedersen, Ken Steen; Hansen, Christian Fink; Denwood, Matthew; Hjulsager, Charlotte Kristiane; Nielsen, Jens Peter

2017-02-01

Previous research projects have demonstrated the need for better diagnostic tools to support decisions on medication strategies for infections caused by Escherichia coli F4 (F4) and F18 (F18), Lawsonia intracellularis (LI) and Brachyspira pilosicoli (PILO). This study was carried out as a randomised clinical trial in three Danish pig herds and included 1047 nursery pigs, distributed over 10 batches and 78 pens. The objectives of this study were: (1) to assess the effect of four 5-day treatment strategies (initiated at clinical outbreak of diarrhoea or at fixed time points 14, 21, or 28days after weaning) on average daily weight gain (ADG); (2) to compare the effect of treatment with doxycycline or tylosine on diarrhoea prevalence, pathogenic bacterial load, and ADG; (3) to evaluate PCR testing of faecal pen floor samples as a diagnostic tool for determining the optimal time of treatment. (1) The four treatment strategies had a significant overall effect on ADG (p=0.01). Pigs starting treatment 14days after weaning had a significantly higher ADG (42 g) compared to pigs treated on day 28 (p=0.01). (2) When measured 2days after treatment, doxycycline treatment resulted in fewer LI-positive pens (p=0.004), lower excretion levels of LI (p=0.013), and fewer pens with a high level of LI (p=0.031) compared to pens treated with tylosine. There was no significant difference in F4, F18 and PILO levels after treatment with the two antibiotic compounds. There was a significant difference (p=0.04) of mean diarrhoea prevalence on day 21 of the study between pens treated with tylosine (0.254, 95% CI: 0.184-0.324), and doxycycline (0.167, 95% CI: 0.124-0.210). The type of antibiotic compound was not found to have a significant effect on ADG (p=0.209). (3) Pigs starting treatment on day 14 in pens where F4, F18, LI or PILO were detected by qPCR on the pen floor had a statistically significant increase in ADG (66g) compared to pigs treated on day 14 in pens where no enteric pathogens

Short communication: In vitro antimicrobial susceptibility of Mycoplasma bovis isolates identified in milk from dairy cattle in Belgium, Germany, and Italy.

PubMed

Barberio, A; Flaminio, B; De Vliegher, S; Supré, K; Kromker, V; Garbarino, C; Arrigoni, N; Zanardi, G; Bertocchi, L; Gobbo, F; Catania, S; Moroni, P

2016-08-01

The objective of this study was to assess the in vitro antimicrobial susceptibility of 73 isolates of Mycoplasma bovis isolated from milk of dairy cattle herds of Belgium, Germany, and Italy. Minimal inhibitory concentration (MIC) values were determined by the microbroth dilution method for the following antimicrobials: erythromycin, spiramycin, tilmicosin, tylosin, lincomycin, enrofloxacin, doxycycline, oxytetracycline, florfenicol, and tiamulin. Macrolides, florfenicol, oxytetracycline, and enrofloxacin, were chosen because they represent antimicrobials families commonly used in several countries for treatment of M. bovis, and their MIC values in cattle population are reported in several studies, allowing a comparison with previous data. Doxycycline and tiamulin were selected to assess the susceptibility of M. bovis to new antimicrobials, because they are not registered in the European Union for the treatment of dairy cattle. Among the agents of the different antimicrobial classes, the macrolides showed the highest concentration to inhibit 90% of isolates (MIC90), all above the highest concentration tested: >8μg/mL for erythromycin, >16μg/mL for spiramycin, and >32μg/mL for tilmicosin and tylosin. Also the MIC90 of lincomycin was above the highest concentration tested (>32μg/mL), but the distribution of the MIC values was almost perfectly bimodal: 41 isolates had a MIC ≤0.5μg/mL and 30 isolates >32μg/mL. Oxytetracycline had a 2-fold higher concentration to inhibit 50% of isolates (2 vs. 0.5μg/mL) and 1-fold higher MIC90 (4 vs. 2μg/mL) than doxycycline. Enrofloxacin and florfenicol had both a MIC90 of 2μg/mL, whereas tiamulin had a MIC90 of 0.5μg/mL. Significant differences on the MIC values were found among the 3 countries for several antimicrobials: compared with Germany, Belgium and Italy showed significantly higher MIC for lincomycin, spiramycin, and tylosin, and lower for oxytetracycline and florfenicol. The Belgian isolates showed the lowest MIC

[Considerations on the antibiotic activity (M.I.C.) revealed in 247 serotypes of Salmonella].

PubMed

Pitzus, E; Peretti, P; Ghinelli, P; Bisicchia, R; Turano, A

1975-01-01

247 strains of Salmonella, isolated in Brescia province duriing 1973-1974 have been typed by serological methods. The MIC has been determined, using the following antibiotics: chloramphenicol, tetracycline HCL, ampicillin, doxycycline, rifampicin, cephazolin, carbenicillin, nifuratel, gentamicin, aminosidine, trimetho-prim-sulphamethoazole, nalidixic acid. The pattern of resistence of the various serotypes is quite constant. The relationship between diffusion and epidermiological factors are discussed.

Comparison of Simultaneous Splenic Sample PCR with Blood Sample PCR for Diagnosis and Treatment of Experimental Ehrlichia canis Infection

PubMed Central

Harrus, Shimon; Kenny, Martin; Miara, Limor; Aizenberg, Itzhak; Waner, Trevor; Shaw, Susan

2004-01-01

This report presents evidence that dogs recover from acute canine monocytic ehrlichiosis (CME) after 16 days of doxycycline treatment (10 mg/kg of body weight every 24 h). Blood PCR was as valuable as splenic aspirate PCR for early diagnosis of acute CME. Splenic aspirate PCR was, however, superior to blood PCR for the evaluation of ehrlichial elimination. PMID:15504892

Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma

PubMed Central

Walther, Madlin; Schneider, Björn; Linnebacher, Michael; Classen, Carl Friedrich

2018-01-01

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment. PMID:29352318

[The plague, possible bioterrorist act].

PubMed

Bossi, Philippe; Bricaire, François

2003-05-17

PLAGUE AND BIOWARFARE: Plague is an infection caused by Yersinia pestis. This is a major agent that might be used as a biological weapon. If the bacteria is sprayed, the most frequent clinical form would be pneumonia. If contaminated fleas were used, the bubonic and septicaemic forms would be those observed. Suspicious context A biowarfare act by spraying Y pestis must be suspected when a patient without any risk factors presents with a primary pulmonary form of the disease in a non endemic area. All the patients presenting with a pulmonary form of plague must be hospitalised and isolated in de-pressurised room, at least for the first three days of antibiotherapy. For the other clinical forms, patients must isolated during the first 48 hours of treatment. Treatment must be initiated as rapidly as possible. Strains of Y. pestis are usually sensitive to many antibiotics (streptomycin, gentamicin, doxycycline, ciprofloxacin, chloramphenicol, sulfadiazin, trimethoprime-sulfamethoxazole...). In the case of contact with a spray suspected of containing the plague bacilla, doxycycline or ciprofloxacin can be prescribed. A dead cell vaccine exists, but its efficacy in terms of protection from primary pneumonia appears inadequate.

A cost-effectiveness comparison of the use of antimicrobial agents for treatment or prophylaxis of travelers' diarrhea.

PubMed

Reves, R R; Johnson, P C; Ericsson, C D; DuPont, H L

1988-11-01

We conducted a decision analysis to compare the cost-effectiveness of antimicrobial agents used for treatment with their use for prophylaxis of travelers' diarrhea. Estimates of the likelihood and the cost of various outcomes were obtained from a panel of experts using the Delphi group opinion technique. Treatment with sulfamethoxazole-trimethoprim for three days was compared with daily prophylaxis with sulfamethoxazole-trimethoprim or doxycycline. The cost-effectiveness of prophylaxis with either agent (75% to 83%) was greater than that of treatment (38%). Treatment would become more cost-effective than prophylaxis when the cumulative risk of acquiring travelers' diarrhea was less than 0.05 episodes per person per week or if the effectiveness of prophylaxis fell below 35% for doxycycline and 46% for sulfamethoxazole-trimethoprim. The most important contributor to the mean cost of travelers' diarrhea in this analysis was the cost associated with a day of incapacitation due to illness. On the basis of the results of this decision analysis, we conclude that prophylaxis of travelers' diarrhea is an option that should be considered for individual situations and recommend further studies of its cost-effectiveness.

Inhibition of matrix metalloproteinase-2 by PARP inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D.

2009-10-02

Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparablemore » to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.« less

Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene-trap mouse model.

PubMed

O'Donnell, Kathryn A; An, Wenfeng; Schrum, Christina T; Wheelan, Sarah J; Boeke, Jef D

2013-07-16

A codon-optimized mouse LINE-1 element, ORFeus, exhibits dramatically higher retrotransposition frequencies compared with its native long interspersed element 1 counterpart. To establish a retrotransposon-mediated mouse model with regulatable and potent mutagenic capabilities, we generated a tetracycline (tet)-regulated ORFeus element harboring a gene-trap cassette. Here, we show that mice expressing tet-ORFeus broadly exhibit robust retrotransposition in somatic tissues when treated with doxycycline. Consistent with a significant mutagenic burden, we observed a reduced number of double transgenic animals when treated with high-level doxycycline during embryogenesis. Transgene induction in skin resulted in a white spotting phenotype due to somatic ORFeus-mediated mutations that likely disrupt melanocyte development. The data suggest a high level of transposition in melanocyte precursors and consequent mutation of genes important for melanoblast proliferation, differentiation, or migration. These findings reveal the utility of a retrotransposon-based mutagenesis system as an alternative to existing DNA transposon systems. Moreover, breeding these mice to different tet-transactivator/reversible tet-transactivator lines supports broad functionality of tet-ORFeus because of the potential for dose-dependent, tissue-specific, and temporal-specific mutagenesis.

Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

PubMed

Feng, Jian; Liu, Jian-Ping; Miao, Li; He, Guo-Xiang; Li, De; Wang, Hai-Dong; Jing, Tao

2014-10-01

Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI.

Tropheryma whipplei tricuspid endocarditis: a case report and review of the literature.

PubMed

Gabus, Vincent; Grenak-Degoumois, Zita; Jeanneret, Severin; Rakotoarimanana, Riana; Greub, Gilbert; Genné, Daniel

2010-08-04

The main clinical manifestations of Whipple's disease are weight loss, arthropathy, diarrhea and abdominal pain. Cardiac involvement is frequently described. However, endocarditis is rare and is not usually the initial presentation of the disease. To the best of our knowledge, this is the first reported case of a patient with Tropheryma whipplei tricuspid endocarditis without any other valve involved and not presenting signs of arthralgia and abdominal involvement. We report a case of a 50-year-old Caucasian man with tricuspid endocarditis caused by Tropheryma whipplei, showing signs of severe shock and an absence of other more classic clinical signs of Whipple's disease, such as arthralgia, abdominal pain and diarrhea. Tropheryma whipplei was documented by polymerase chain reaction of the blood and pleural fluid. The infection was treated with a combined treatment of doxycycline, hydroxychloroquine and sulfamethoxazole-trimethoprim for one year. Tropheryma whipplei infectious endocarditis should always be considered when facing a blood-culture negative endocarditis particularly in right-sided valves. Although not standardized yet, treatment of Tropheryma whipplei endocarditis should probably include a bactericidal antibiotic (such as doxycycline) and should be given over a prolonged period of time (a minimum of one year).

An all-in-one, Tet-On 3G inducible PiggyBac system for human pluripotent stem cells and derivatives.

PubMed

Randolph, Lauren N; Bao, Xiaoping; Zhou, Chikai; Lian, Xiaojun

2017-05-08

Human pluripotent stem cells (hPSCs) offer tremendous promise in tissue engineering and cell-based therapies due to their unique combination of two properties: pluripotency and unlimited proliferative capacity. However, directed differentiation of hPSCs to clinically relevant cell lineages is needed to achieve the goal of hPSC-based therapies. This requires a deep understanding of how cell signaling pathways converge on the nucleus to control differentiation and the ability to dissect gene function in a temporal manner. Here, we report the use of the PiggyBac transposon and a Tet-On 3G drug-inducible gene expression system to achieve versatile inducible gene expression in hPSC lines. Our new system, XLone, offers improvement over previous Tet-On systems with significantly reduced background expression and increased sensitivity to doxycycline. Transgene expression in hPSCs is tightly regulated in response to doxycycline treatment. In addition, the PiggyBac elements in our XLone construct provide a rapid and efficient strategy for generating stable transgenic hPSCs. Our inducible gene expression PiggyBac transposon system should facilitate the study of gene function and directed differentiation in human stem cells.

Confirmed inguinal lymphogranuloma venereum genovar L2c in a man who had sex with men, Slovenia, 2015.

PubMed

Matičič, Mojca; Klavs, Irena; Videčnik Zorman, Jerneja; Vidmar Vovko, Darja; Kogoj, Rok; Keše, Darja

2016-01-01

A laboratory-confirmed lymphogranuloma venereum (LGV) case in Slovenia was reported in 2015, in a human immunodeficiency virus (HIV)-negative man presenting with inguinal lymphadenopathy. He reported unprotected insertive anal intercourse with two male partners in Croatia. Variant L2c of Chlamydia trachomatis was detected in clinical samples. Although the patient was eventually cured, the recommended treatment regimen with doxycycline had to be prolonged.

3D Microperfusion Model of ADPKD

DTIC Science & Technology

2017-06-01

approaches. These included utilizing an alternative immortalized renal cortical epithelial cell line (RPTEC/tert1 from ATCC) and advances in CRISPR /Cas9 to...expression 48 hours  after doxycycline treatment.  Figure  5. RPTEC/TERT1 cells 48 hours after  transfection with  a polycystin‐1  CRISPR /Cas9

Risk of Relapse Associated with Doxycycline Therapy for Scrub Typhus

DTIC Science & Technology

1981-01-01

143150-9 202 Rickettsiae ard Rickettsial Diseases I. INTRODUCTION Chloramphenicol (Chloromycetin) or oxytetracycline (Terra- mycin) are the drugs...doses of oxytetracycline in a double blind, randomized trial conducted in a population of scrub typhus patients who were exposed in the Pescadores... oxytetracycline , 500 mg every 6 hrs for 7 days (OXY, 23 patients). Drug and placebo were manufactured in such a way and administered every 6 hrs for 7

Comparative analysis on antibiotic resistance characteristics of Listeria spp. and Enterococcus spp. isolated from laying hens and eggs in conventional and organic keeping systems in Bavaria, Germany.

PubMed

Schwaiger, K; Schmied, E-M V; Bauer, J

2010-05-01

By investigating the prevalence and antimicrobial resistance characteristics of Gram-positive bacteria from organic and conventional keeping systems of laying hens, it was to be determined to what extent these properties are influenced by the different systems. For this purpose, a total of 799 cloacal swabs and 800 egg samples were examined. Prevalences for all selected bacteria from cloacal swabs were much the same for both organic and caged birds: Listeria spp.1.3%[org] versus 1.6%[con]; Enterococcus spp. 95.5%[org] versus 97.5%[con]. Egg contents and eggshells were generally contaminated to a lesser extent, primarily with Enterococcus spp. Listeria isolates were susceptible to almost all tested antibiotics, only three Listeria innocua from conventional keepings were resistant to clindamycin; one isolate additionally to imipenem. High percentages of Enterococcus faecalis were resistant to doxycycline and macrolides. Enterococcus faecium proved to have high resistance rates to clindamycin, fosfomycin and erythromycin; 9.1% were even resistant to the reserve antibiotic synercid. Further, Enterococcus spp. showed higher resistance rates to doxycycline, erythromycin, fosfomycin and rifampicin. No glycopeptide resistant enterococci were detected. A correlation between keeping system and resistance/susceptibility rates could be demonstrated. In detail, E. faecalis from organic laying hen husbandries showed significant lower resistance prevalences to tylosin, streptomycin and doxycycline; susceptibility rates were higher for enrofloxacin and ciprofloxacin. Rifampicin and imipenem were more effective in isolates from conventional keepings (P < 0.05). The amounts of resistant isolates of the Enterococcus raffinosus from organic farms were significantly lower, the amounts of sensitive isolates were significantly higher than from conventional farms concerning eight antibiotics (P < 0.05). When comparing the susceptibility/resistance rates, as well as the mean minimum

Dogs Leaving the ICU Carry a Very Large Multi-Drug Resistant Enterococcal Population with Capacity for Biofilm Formation and Horizontal Gene Transfer

PubMed Central

Ghosh, Anuradha; Dowd, Scot E.; Zurek, Ludek

2011-01-01

The enterococcal community from feces of seven dogs treated with antibiotics for 2–9 days in the veterinary intensive care unit (ICU) was characterized. Both, culture-based approach and culture-independent 16S rDNA amplicon 454 pyrosequencing, revealed an abnormally large enterococcal community: 1.4±0.8×108 CFU gram−1 of feces and 48.9±11.5% of the total 16,228 sequences, respectively. The diversity of the overall microbial community was very low which likely reflects a high selective antibiotic pressure. The enterococcal diversity based on 210 isolates was also low as represented by Enterococcus faecium (54.6%) and Enterococcus faecalis (45.4%). E. faecium was frequently resistant to enrofloxacin (97.3%), ampicillin (96.5%), tetracycline (84.1%), doxycycline (60.2%), erythromycin (53.1%), gentamicin (48.7%), streptomycin (42.5%), and nitrofurantoin (26.5%). In E. faecalis, resistance was common to tetracycline (59.6%), erythromycin (56.4%), doxycycline (53.2%), and enrofloxacin (31.9%). No resistance was detected to vancomycin, tigecycline, linezolid, and quinupristin/dalfopristin in either species. Many isolates carried virulence traits including gelatinase, aggregation substance, cytolysin, and enterococcal surface protein. All E. faecalis strains were biofilm formers in vitro and this phenotype correlated with the presence of gelE and/or esp. In vitro intra-species conjugation assays demonstrated that E. faecium were capable of transferring tetracycline, doxycycline, streptomycin, gentamicin, and erythromycin resistance traits to human clinical strains. Multi-locus variable number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE) of E. faecium strains showed very low genotypic diversity. Interestingly, three E. faecium clones were shared among four dogs suggesting their nosocomial origin. Furthermore, multi-locus sequence typing (MLST) of nine representative MLVA types revealed that six sequence types (STs) originating from five

FOXO1 is a direct target of EWS-Fli1 oncogenic fusion protein in Ewing's sarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Liu, E-mail: lyang@u.washington.edu; Medical Research Service, VA Puget Sound Health Care System, Seattle, WA 98108; Hu, Hsien-Ming

2010-11-05

Research highlights: {yields} Inducible and reversible siRNA knockdown of an oncogenic fusion protein such as EWS-Fli1 is feasible and more advantageous than other siRNA methods. {yields} The tumor suppressor gene FOXO1 is a new EWS-Fli1 target. {yields} While trans-activators are known for the FOXO1 gene, there has been no report on negative regulators of FOXO1 transcription. {yields} This study provides first evidence that the EWS-Fli1 oncogenic fusion protein can function as a transcriptional repressor of the FOXO1 gene. -- Abstract: Ewing's family tumors are characterized by a specific t(11;22) chromosomal translocation that results in the formation of EWS-Fli1 oncogenic fusionmore » protein. To investigate the effects of EWS-Fli1 on gene expression, we carried out DNA microarray analysis after specific knockdown of EWS-Fli1 through transfection of synthetic siRNAs. EWS-Fli1 knockdown increased expression of genes such as DKK1 and p57 that are known to be repressed by EWS-Fli1 fusion protein. Among other potential EWS-Fli1 targets identified by our microarray analysis, we have focused on the FOXO1 gene since it encodes a potential tumor suppressor and has not been previously reported in Ewing's cells. To better understand how EWS-Fli1 affects FOXO1 expression, we have established a doxycycline-inducible siRNA system to achieve stable and reversible knockdown of EWS-Fli1 in Ewing's sarcoma cells. Here we show that FOXO1 expression in Ewing's cells has an inverse relationship with EWS-Fli1 protein level, and FOXO1 promoter activity is increased after doxycycline-induced EWS-Fli1 knockdown. In addition, we have found that direct binding of EWS-Fli1 to FOXO1 promoter is attenuated after doxycycline-induced siRNA knockdown of the fusion protein. Together, these results suggest that suppression of FOXO1 function by EWS-Fli1 fusion protein may contribute to cellular transformation in Ewing's family tumors.« less

Probabilistic risk model to assess the potential for resistance selection following the use of anti-microbial medicated feed in pigs.

PubMed

Filippitzi, Maria Eleni; Chantziaras, Ilias; Devreese, Mathias; Dewulf, Jeroen

2018-05-30

The cross-contamination of non-medicated feed with residues of anti-microbials (AM) causes a public and animal health concern associated with the potential for selection and dissemination of resistance. To analyse the associated risks, a probabilistic model was built using @Risk® (Palisade Corporation®) to show the potential extent of the effect of cross-contaminated pig feed on resistance selection. The results of the model include estimations of the proportion of pigs per production stage with residues of doxycycline, chlortetracycline, sulfadiazine and trimethoprim in their intestinal contents, as a result of exposure to cross-contaminated feed with different carry-over levels, in Belgium. By using a semi-quantitative approach, these estimations were combined with experimental data on AM concentrations associated with potential for resistance-selection pressure. Based on this model, it is estimated that 7.76% (min = 1.67; max = 36.94) of sows, 4.23% (min = 1.01%; max = 18.78%) of piglets and 2.8% (min = 0.51%; max = 14.9%) of fatteners in Belgium have residues of doxycycline in their intestinal tract due to consumption of feed with at least 1% carry-over. These values were estimated to be almost triple for sulfadiazine, but substantially lower for chlortetracycline and trimethoprim. Doxycycline concentrations as low as 1 mg/L (corresponding to consumed feed with at least 1% carry-over) can select for resistant porcine commensal Escherichia coli in vitro and in vivo. Conclusions on this risk could not be drawn for other AM at this stage, due to the lack of data on concentrations associated with resistance development. However, since the possibility of resistance mechanisms (e.g. co-selection) occurring cannot be excluded, the results of this model highlight that the use of AM medicated feed should be minimised where possible. In case of medicated feed production, good practice should be followed thoroughly at all levels of production, distribution

Role of Endotoxin in the Pathogenesis of Louse-borne Relapsing Fever and in the Mechanism of the Jarisch-Herxheimer Reaction Following Treatment of Louse-borne Relapsing Fever

DTIC Science & Technology

1977-12-01

therapy and during the Jarisch-Herxheimer-like reaction. Further similarities between relapsing fever and Gram-negative bacteremic diseases were sought by...activated during Gram- negative bacterial infections (11-17). The aims of therapy should be to clear the blood of circulating spirochetes without relapse and...more slowly with more prolonged fever. Single dose therapy with intravenous tetracycline [1,2] and oral doxycycline [18] has been shown effective, but

Severe glandular tularemia in a patient treated with anti-tumour necrosis factor for psoriatic arthritis.

PubMed

Calin, Ruxandra; Caumes, Eric; Reibel, Florence; Ali Mohamed, Anzime; Brossier, Florence; Foltz, Violaine; Boussouar, Samia; Fautrel, Bruno; Maurin, Max; Katlama, Christine; Pourcher, Valérie

2017-07-01

A case of severe glandular tularemia in a patient receiving anti-tumour necrosis factor (TNF) therapy is reported here. The patient required prolonged treatment with doxycycline-ciprofloxacin due to early relapse after ciprofloxacin was stopped. Tularemia may have a more severe course in patients receiving anti-TNF. This may thus be an indication for more aggressive treatment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Subtotal Ablation of Parietal Epithelial Cells Induces Crescent Formation

PubMed Central

Sicking, Eva-Maria; Fuss, Astrid; Uhlig, Sandra; Jirak, Peggy; Dijkman, Henry; Wetzels, Jack; Engel, Daniel R.; Urzynicok, Torsten; Heidenreich, Stefan; Kriz, Wilhelm; Kurts, Christian; Ostendorf, Tammo; Floege, Jürgen; Smeets, Bart

2012-01-01

Parietal epithelial cells (PECs) of the renal glomerulus contribute to the formation of both cellular crescents in rapidly progressive GN and sclerotic lesions in FSGS. Subtotal transgenic ablation of podocytes induces FSGS but the effect of specific ablation of PECs is unknown. Here, we established an inducible transgenic mouse to allow subtotal ablation of PECs. Proteinuria developed during doxycycline-induced cellular ablation but fully reversed 26 days after termination of doxycycline administration. The ablation of PECs was focal, with only 30% of glomeruli exhibiting histologic changes; however, the number of PECs was reduced up to 90% within affected glomeruli. Ultrastructural analysis revealed disruption of PEC plasma membranes with cytoplasm shedding into Bowman’s space. Podocytes showed focal foot process effacement, which was the most likely cause for transient proteinuria. After >9 days of cellular ablation, the remaining PECs formed cellular extensions to cover the denuded Bowman’s capsule and expressed the activation marker CD44 de novo. The induced proliferation of PECs persisted throughout the observation period, resulting in the formation of typical cellular crescents with periglomerular infiltrate, albeit without accompanying proteinuria. In summary, subtotal ablation of PECs leads the remaining PECs to react with cellular activation and proliferation, which ultimately forms cellular crescents. PMID:22282596

A 6-year-old girl with fever, rash, and increased intracranial pressure.

PubMed

Ravish, Matthew E; Krowchuk, Daniel P; Zapadka, Michael; Shetty, Avinash K

2013-08-01

Rocky Mountain spotted fever (RMSF) is a well-described, potentially lethal, tick-borne zoonotic infection and has very effective therapy. However, the diagnosis might not be made early enough, often leading to worse outcomes. Our aim was to discuss the diagnostic dilemmas facing the physician when evaluating patients with suspected RMSF. We report a case of RMSF in a 6-year-old girl who presented to our hospital with a 7-day history of fever, headache, and a petechial rash. After blood cultures were obtained, the patient was treated empirically with doxycycline, vancomycin, and ceftriaxone. During the next 24 h, her clinical status worsened, with acute onset of altered mental status, posturing, and fixed and dilated pupils. A computed tomography scan of the brain demonstrated diffuse cerebral edema with evidence of tonsillar herniation. She died 24 h after admission. A serum specimen tested positive for immunoglobulin G to Rickettsia rickettsii at a titer of 128 dilutions, confirming recent infection. We present this case to raise awareness of RMSF in patients who present with a nonspecific febrile illness in tick-endemic areas in the United States. Early diagnosis and treatment with doxycycline before day 5 of illness is essential and can prevent morbidity and mortality. Copyright © 2013 Elsevier Inc. All rights reserved.

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

PubMed Central

Yao, Li-Chin; Flores, Julio C.; Choi, Dongwon; Hong, Young-Kwon; McDonald, Donald M.

2017-01-01

Lymphatic malformations are serious but poorly understood conditions that present therapeutic challenges. The goal of this study was to compare strategies for inducing regression of abnormal lymphatics and explore underlying mechanisms. CCSP-rtTA/tetO-VEGF-C mice, in which doxycycline regulates VEGF-C expression in the airway epithelium, were used as a model of pulmonary lymphangiectasia. After doxycycline was stopped, VEGF-C expression returned to normal, but lymphangiectasia persisted for at least 9 months. Inhibition of VEGFR-2/VEGFR-3 signaling, Notch, β-adrenergic receptors, or autophagy and antiinflammatory steroids had no noticeable effect on the amount or severity of lymphangiectasia. However, rapamycin inhibition of mTOR reduced lymphangiectasia by 76% within 7 days without affecting normal lymphatics. Efficacy of rapamycin was not increased by coadministration with the other agents. In prevention trials, rapamycin suppressed VEGF-C–driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation. However, in reversal trials, no lymphatic endothelial cell proliferation was present to block in established lymphangiectasia, and rapamycin did not increase caspase-dependent apoptosis. However, rapamycin potently suppressed Prox1 and VEGFR-3. These experiments revealed that lymphangiectasia is remarkably resistant to regression but is responsive to rapamycin, which rapidly reduces and normalizes the abnormal lymphatics without affecting normal lymphatics. PMID:28814666

Development of an intracanal mature Enterococcus faecalis biofilm and its susceptibility to some antimicrobial intracanal medications; an in vitro study

PubMed Central

Saber, Shehab El-Din Mohamed; El-Hady, Soha A.

2012-01-01

Objectives: To develop a mature biofilm of Enterococcus faecalis inside the root canal system and to test its susceptibility to some antimicrobial medications in vitro. Methods: Single rooted premolars were mechanically enlarged, sterilized, and then infected with a clinical isolate of E. faecalis. Biofilm formation and maturation was monitored using SEM. Biofilm bacteria were exposed to Amoxicillin+clavulanate, Ciprofloxacin, Clindamycin, Doxycycline, and calcium hydroxide as intracanal medications for 1 week. Finally bacterial samples were collected, and colony-forming units were enumerated. Results: SEM examination confirmed the formation of a mature biofilm at the end of the incubation period. All the chemotherapeutic agents used were significantly better than Calcium hydroxide in elimination of biofilm bacteria. The antimicrobial effect of Amoxicillin + clavulanate, Ciprofloxacin and Clindamycin was significantly better than Doxycycline (P=.05). However the difference in the antimicrobial effectiveness among them was statistically non-significant (P=.05). Conclusions: The method used for bacterial biofilm development and maturation is reliable and can be used to assess the anti bacterial potential of endodontic materials. Also, the local application of antibacterial agents can be beneficial in resistant cases of apical periodontitis but only after careful culture and sensitivity testing to choose the appropriate agent for the existing flora. PMID:22229006

Inhibition of Legionella pneumophila multiplication within human macrophages by antimicrobial agents.

PubMed Central

Vildé, J L; Dournon, E; Rajagopalan, P

1986-01-01

The activity of serial concentrations of different antimicrobial agents on the multiplication of Legionella pneumophila within human monocyte-derived macrophages was studied. The results led to the definition of a minimal extracellular concentration inhibiting intracellular multiplication (MIEC). According to the MIECs, the antimicrobial agents tested were classified in three groups: very active (MIEC less than or equal to 0.06 microgram/ml), such as erythromycin, rifampin, and pefloxacin; active (1 microgram/ml greater than or equal to MIEC greater than or equal to 0.1 microgram/ml), such as sulfamethoxazole-trimethoprim or doxycycline; and ineffective, such as cefoxitin, which was not active within macrophages at as high as 64 micrograms/ml despite a low MIC (0.2 microgram/ml) on bacterial charcoal-yeast extract agar. The activity of netilmicin was difficult to assess because of its effect on extracellular legionellae. Combinations of erythromycin with rifampin and pefloxacin with erythromycin, rifampin, doxycycline, or netilmicin showed an additive effect and no antagonism. These results obtained in a cellular model are in agreement with the efficacy of antimicrobial agents in experimental infections and in Legionnaires disease. They sustain clinical interest in the new quinolones, such as pefloxacin, and in combinations of antimicrobial agents for the treatment of Legionnaires disease. PMID:3492176

Studies on a suitable antibiotic therapy for treating swine brucellosis.

PubMed

Dieste-Pérez, L; Fraile, L; de Miguel, M J; Barberán, M; Blasco, J M; Muñoz, P M

2015-08-01

The aim of this work was developing effective treatments against Brucella suis biovar 2, responsible for swine brucellosis in Europe. MICs for antibiotics used classically in brucellosis and two new macrolides (tulathromycin and tildipirosin) were determined for 33 B. suis biovar 2 field and B. suis reference strains. MIC90 values ranged from 0.01 to 0.25 μg/mL. The best candidates, given alone or combined, were then evaluated in mice. Ten groups (n = 7) of BALB/c mice were inoculated (1 × 10(5) CFU/mouse) with a virulent B. suis biovar 2 field strain. All groups, excepting untreated control, were treated for 14 days with, respectively, doxycycline, dihydrostreptomycin, tulathromycin (one or two doses), or tildipirosin (one or two doses) given alone, and doxycycline combined with dihydrostreptomycin, tulathromycin, or tildipirosin. Combined tildipirosin treatment was the most effective, then selected for pig studies. Sixteen B. suis biovar 2 naturally infected sows were treated with oxytetracycline (20 mg/kg BW/daily) for 21 days. The half of these received also tildipirosin (4 mg/kg BW) in two doses with a 10-day interval. An extensive bacteriological study conducted ten days after ceasing treatments proved the efficacy of this combined oxytetracycline/tildipirosin treatment. © 2014 John Wiley & Sons Ltd.

In vitro activity of five tetracyclines and some other antimicrobial agents against four porcine respiratory tract pathogens.

PubMed

Pijpers, A; Van Klingeren, B; Schoevers, E J; Verheijden, J H; Van Miert, A S

1989-09-01

The minimal inhibitory concentrations (MIC) of five tetracyclines and ten other antimicrobial agents were determined for four porcine bacterial respiratory tract pathogens by the agar dilution method. For the following oxytetracycline-susceptible strains, the MIC50 ranges of the tetracyclines were: P. multocida (n = 17) 0.25-0.5 micrograms/ml; B. bronchiseptica (n = 20) 0.25-1.0 micrograms/ml; H. pleuropneumoniae (n = 20) 0.25-0.5 micrograms/ml; S. suis Type 2 (n = 20) 0.06-0.25 micrograms/ml. For 19 oxytetracycline-resistant P. multocida strains the MIC50 of the tetracyclines varied from 64 micrograms/ml for oxytetracycline to 0.5 micrograms/ml for minocycline. Strikingly, minocycline showed no cross-resistance with oxytetracycline, tetracycline, chlortetracycline and doxycycline in P. multocida and in H. pleuropneumoniae. Moreover, in susceptible strains minocycline showed the highest in vitro activity followed by doxycycline. Low MIC50 values were observed for chloramphenicol, ampicillin, flumequine, ofloxacin and ciprofloxacin against P. multocida and H. pleuropneumoniae. B. bronchiseptica was moderately susceptible or resistant to these compounds. As expected tiamulin, lincomycin, tylosin and spiramycin were not active against H. pleuropneumoniae. Except for flumequine, the MIC50 values of nine antimicrobial agents were low for S. suis Type 2. Six strains of this species showed resistance to the macrolides and lincomycin.

Immunohistological studies on neoplasms of female and male Onchocerca volvulus: filarial origin and absence of Wolbachia from tumor cells

PubMed Central

BRATTIG, N. W.; HOERAUF, A.; FISCHER, P. U.; LIEBAU, E.; BANDI, C.; DEBRAH, A.; BÜTTNER, M.; BÜTTNER, D. W.

2010-01-01

SUMMARY Up to 5% of untreated female Onchocerca volvulus filariae develop potentially fatal pleomorphic neoplasms, whose incidence is increased following ivermectin treatment. We studied the occurrence of 8 filarial proteins and of Wolbachia endobacteria in the tumor cells. Onchocercomas from patients, untreated and treated with antibiotics and anthelminthics, were examined by immunohistology. Neoplasms were diagnosed in 112 of 3587 female and in 2 of 1570 male O. volvulus. The following proteins and other compounds of O. volvulus were expressed in the cells of the neoplasms: glutathione S-transferase 1, lysosomal aspartic protease, cAMP-dependent protein kinase, alpha-enolase, aspartate aminotransferase, ankyrin E1, tropomyosin, heat shock protein 60, transforming growth factor-beta, and prostaglandin E2. These findings prove the filarial origin of the neoplasms and confirm the pleomorphism of the tumor cells. Signs indicating malignancy of the neoplasms are described. Wolbachia were observed in the hypodermis, oocytes, and embryos of tumor-harbouring filariae using antibodies against Wolbachia surface protein, Wolbachia HtrA-type serine protease, and Wolbachia aspartate aminotransferase. In contrast, Wolbachia were not found in the cells of the neoplasms. Further, neoplasm-containing worms were not observed after more than 10 months after the start of sufficient treatment with doxycycline or doxycycline plus ivermectin. PMID:20199697

Inducible expression of photoacoustic reporter gene tyrosinase in cells using a single plasmid

NASA Astrophysics Data System (ADS)

Paproski, Robert J.; Zemp, Roger J.

2012-02-01

We have previously demonstrated that tyrosinase is a reporter gene for photoacoustic imaging since tyrosinase is the rate-limiting step in the synthesis of melanin, a pigment capable of producing strong photoacoustic signals. We previously created a cell line capable of inducible tyrosinase expression (important due to toxicity of melanin) by stably transfecting tyrosinase in MCF-7 Tet-OnR cell line (Clontech) which expresses a doxycycline-controlled transactivator. Unfortunately, Clontech provides few Tet-On Advanced cell lines making it difficult to have inducible tyrosinase expression in cell lines not provided by Clontech. In order to simplify the creation of cell lines with inducible expression of tyrosinase, we created a single plasmid that encodes both the transactivator as well as tyrosinase. PCR was used to amplify both the transactivator and tyrosinase from the Tet-OnR Advanced and pTRE-Tight-TYR plasmids, respectively. Both PCR products were cloned into the pEGFP-N1 plasmid and the newly created plasmid was transfected into ZR-75-1, MCF-7, and MIA PaCa-1 cells using lipofectamine. After several days, brown melanin was only observed in cells incubated with doxycycline, suggesting that the newly created single plasmid allowed inducible tyrosinase expression in many different cells lines.

Multidrug-resistant gram-negative bacteria colonization of healthy US military personnel in the US and Afghanistan.

PubMed

Vento, Todd J; Cole, David W; Mende, Katrin; Calvano, Tatjana P; Rini, Elizabeth A; Tully, Charla C; Zera, Wendy C; Guymon, Charles H; Yu, Xin; Cheatle, Kristelle A; Akers, Kevin S; Beckius, Miriam L; Landrum, Michael L; Murray, Clinton K

2013-02-05

The US military has seen steady increases in multidrug-resistant (MDR) gram-negative bacteria (GNB) infections in casualties from Iraq and Afghanistan. This study evaluates the prevalence of MDR GNB colonization in US military personnel. GNB colonization surveillance of healthy, asymptomatic military personnel (101 in the US and 100 in Afghanistan) was performed by swabbing 7 anatomical sites. US-based personnel had received no antibiotics within 30 days of specimen collection, and Afghanistan-based personnel were receiving doxycycline for malaria chemoprophylaxis at time of specimen collection. Isolates underwent genotypic and phenotypic characterization. The only colonizing MDR GNB recovered in both populations was Escherichia coli (p=0.01), which was seen in 2% of US-based personnel (all perirectal) and 11% of Afghanistan-based personnel (10 perirectal, 1 foot+groin). Individuals with higher off-base exposures in Afghanistan did not show a difference in overall GNB colonization or MDR E. coli colonization, compared with those with limited off-base exposures. Healthy US- and Afghanistan-based military personnel have community onset-MDR E. coli colonization, with Afghanistan-based personnel showing a 5.5-fold higher prevalence. The association of doxycycline prophylaxis or other exposures with antimicrobial resistance and increased rates of MDR E. coli colonization needs further evaluation.

[Brucellosis in Chile: Description of a series of 13 cases].

PubMed

Olivares, Roberto; Vidal, Pamela; Sotomayor, Camila; Norambuena, Mackarenna; Luppi, Mario; Silva, Francisco; Cifuentes, Marcela

2017-06-01

Brucellosis is a zoonosis caused by Brucella spp. It may be acquired by consuming unpasteurized dairy products. Brucellosis has a low incidence in Chile, thus, we have a scarce data. To report and to characterize the first series of clinical cases of adult patients diagnosed with brucellosis in Chile. We describe a series of 13 clinical cases in patients diagnosed between 2000 and 2016 in three different centers in the Metropolitan Region, Chile. A retrospective analysis was performed on clinical presentation, laboratory, antibiotic treatment, morbidity and mortality. The mean age was 50 years old. Eight cases had a record of consumption of unpasteurized dairy products. The most frequently reported complaints were fever. The most frequent focal point involved was the spine. Only one patient had a positive blood culture, while the diagnosis was made using serological techniques in the other part of the group. The most indicated antibiotic regimens were doxycycline-rifampicin and doxycycline-gentamicin. The hospital stay was 20 days approximately as an average. Clinical cure was achieved in all cases. Brucellosis is an infrequent zoonosis in Chile, and it produces a nonspecific clinical picture, so it is necessary to have high suspicion to make the diagnosis based in the antecedent of consumption of unpasteurized dairy or raw meat.

Tropheryma whipplei tricuspid endocarditis: a case report and review of the literature

PubMed Central

2010-01-01

Introduction The main clinical manifestations of Whipple's disease are weight loss, arthropathy, diarrhea and abdominal pain. Cardiac involvement is frequently described. However, endocarditis is rare and is not usually the initial presentation of the disease. To the best of our knowledge, this is the first reported case of a patient with Tropheryma whipplei tricuspid endocarditis without any other valve involved and not presenting signs of arthralgia and abdominal involvement. Case presentation We report a case of a 50-year-old Caucasian man with tricuspid endocarditis caused by Tropheryma whipplei, showing signs of severe shock and an absence of other more classic clinical signs of Whipple's disease, such as arthralgia, abdominal pain and diarrhea. Tropheryma whipplei was documented by polymerase chain reaction of the blood and pleural fluid. The infection was treated with a combined treatment of doxycycline, hydroxychloroquine and sulfamethoxazole-trimethoprim for one year. Conclusion Tropheryma whipplei infectious endocarditis should always be considered when facing a blood-culture negative endocarditis particularly in right-sided valves. Although not standardized yet, treatment of Tropheryma whipplei endocarditis should probably include a bactericidal antibiotic (such as doxycycline) and should be given over a prolonged period of time (a minimum of one year). PMID:20684779

Recovery from diabetes in mice by β cell regeneration

PubMed Central

Nir, Tomer; Melton, Douglas A.; Dor, Yuval

2007-01-01

The mechanisms that regulate pancreatic β cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing β cells is often irreversible, adult β cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the β cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of β cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in β cells, resulting in apoptosis of 70%–80% of β cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of β cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving β cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited β cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs. PMID:17786244

Antibacterial activity of moxifloxacin on bacteria associated with periodontitis within a biofilm.

PubMed

Tsaousoglou, Phoebus; Nietzsche, Sandor; Cachovan, Georg; Sculean, Anton; Eick, Sigrun

2014-02-01

The activity of moxifloxacin was compared with ofloxacin and doxycycline against bacteria associated with periodontitis within a biofilm (single strain and mixed population) in vitro. MICs and minimal bactericidal concentrations (MBCs) of moxifloxacin, ofloxacin and doxycyline were determined against single strains and mixed populations in a planktonic state. Single-species biofilms of two Porphyromonas gingivalis and two Aggregatibacter actinomycetemcomitans strains and a multispecies biofilm consisting of 12 species were formed for 3 days. The minimal biofilm eradication concentrations (MBECs) were determined after exposing the biofilms to the antibacterials (0.002-512 µg ml(-1)) for 18 h, addition of nutrient broth for 3 days and subsequent subcultivation. Photographs were taken using confocal laser-scanning microscopy and scanning electron microscopy. The MICs and MBCs did not differ between ofloxacin and moxifloxacin against A. actinomycetemcomitans, whilst moxifloxacin was more active than the other tested antibacterials against anaerobes and the mixed population. The single-species biofilms were eradicated by moderate concentrations of the antibacterials, and the lowest MBECs were always found for moxifloxacin (2-8 µg ml(-1)). MBECs against the multispecies biofilms were 128, >512 and >512 µg ml(-1) for moxifloxacin, ofloxacin and doxycycline, respectively. In summary, moxifloxacin in a topical formulation may have potential as an adjunct to mechanical removal of the biofilms.

Multidrug-resistant gram-negative bacteria colonization of healthy US military personnel in the US and Afghanistan

PubMed Central

2013-01-01

Background The US military has seen steady increases in multidrug-resistant (MDR) gram-negative bacteria (GNB) infections in casualties from Iraq and Afghanistan. This study evaluates the prevalence of MDR GNB colonization in US military personnel. Methods GNB colonization surveillance of healthy, asymptomatic military personnel (101 in the US and 100 in Afghanistan) was performed by swabbing 7 anatomical sites. US-based personnel had received no antibiotics within 30 days of specimen collection, and Afghanistan-based personnel were receiving doxycycline for malaria chemoprophylaxis at time of specimen collection. Isolates underwent genotypic and phenotypic characterization. Results The only colonizing MDR GNB recovered in both populations was Escherichia coli (p=0.01), which was seen in 2% of US-based personnel (all perirectal) and 11% of Afghanistan-based personnel (10 perirectal, 1 foot+groin). Individuals with higher off-base exposures in Afghanistan did not show a difference in overall GNB colonization or MDR E. coli colonization, compared with those with limited off-base exposures. Conclusion Healthy US- and Afghanistan-based military personnel have community onset-MDR E. coli colonization, with Afghanistan-based personnel showing a 5.5-fold higher prevalence. The association of doxycycline prophylaxis or other exposures with antimicrobial resistance and increased rates of MDR E. coli colonization needs further evaluation. PMID:23384348

Minocycline affects human neutrophil respiratory burst and transendothelial migration.

PubMed

Parenti, Astrid; Indorato, Boris; Paccosi, Sara

2017-02-01

This study aimed at investigating the in vitro activity of minocycline and doxycycline on human polymorphonuclear (h-PMN) cell function. h-PMNs were isolated from whole venous blood of healthy subjects; PMN oxidative burst was measured by monitoring ROS-induced oxidation of luminol and transendothelial migration was studied by measuring PMN migration through a monolayer of human umbilical vein endothelial cells. Differences between multiple groups were determined by ANOVA followed by Tukey's multiple comparison test; Student's t test for unpaired data for two groups. Minocycline (1-300 µM) concentration dependently and significantly inhibited oxidative burst of h-PMNs stimulated with 100 nM fMLP. Ten micromolar concentrations, which are superimposable to C max following a standard oral dose of minocycline, promoted a 29.8 ± 4 % inhibition of respiratory burst (P < 0.001; n = 6). Doxycycline inhibited ROS production with a lesser extent and at higher concentrations. 10-100 µM minocycline impaired PMN transendothelial migration, with maximal effect at 100 µM (42.5 ± 7 %, inhibition, n = 5, P < 0.001). These results added new insight into anti-inflammatory effects of minocycline exerted on innate immune h-PMN cell function.

Characterization of Antimicrobial Agent Loaded Eudragit RS Solvent Exchange-Induced In Situ Forming Gels for Periodontitis Treatment.

PubMed

Phaechamud, Thawatchai; Jantadee, Takron; Mahadlek, Jongjan; Charoensuksai, Purin; Pichayakorn, Wiwat

2017-02-01

Eudragit RS (ERS), a quaternary polyacrylate positively charged polymer, exhibits a very low permeability and swells in aqueous media independently of pH without dissolving. Owing to its high solubility in N-methyl pyrrolidone (NMP), it was interesting to apply as polymer matrix for solvent-exchanged in situ forming gel. The aim of this research was to prepare in situ forming gels from ERS to deliver the antimicrobial agents (doxycycline hyclate, metronidazole, and benzoyl peroxide) for periodontitis treatment. They were evaluated for viscosity and rheology, gel formation, syringeability, drug release, and antimicrobial activities. The solvent exchange between NMP and an external aqueous simulated gingival crevicular fluid stimulated the dissolved ERS transforming into the opaque rigid gel. Antimicrobial agent loaded ERS systems exhibited Newtonian flow with acceptable syringeability. The higher-loaded ERS promoted the more prolongation of drug release because of the retardation of water diffusion into the precipitated matrix. Antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyromonas gingivalis depended on type of drugs and test microorganisms. Doxycycline hyclate loaded ERS systems showed these activities greater than the others; however, all of them could inhibit all test microorganisms. Thus, the solvent exchange-induced in situ forming gels comprising ERS-antimicrobial drugs exhibited potential use as localized delivery systems for periodontitis treatment.

NFAT Signaling and the Tumorigenic Microenvironment of the Prostate

DTIC Science & Technology

2016-10-01

Subtask 2: Investigate if NFATc1 promotes the progression of hormone -naïve prostate cancer into castration-resistant prostate cancer 1-18 Drs...combating prostate cancer progression. In order to determine if NFATc1-induced prostate cancer would respond to hormone deprivation therapy, such as...doxycycline (Dox). These tumor cells were then injected to the rear flanks of the nude mice. Recipient mice treated with Dox showed growth of tumor as

3D Microperfusion Model of ADPKD

DTIC Science & Technology

2015-10-01

Stratasys 3D printer. PDMS was cast in the negative molds in order to create permanent biocompatible plastic masters (SmoothCast 310). All goals of task...fabrication was accomplished using a custom multistep fabrication process. A negative mold of the bioreactor, designed in AutoCAD, was created using a...immortalized renal cortical epithelial cells (NKi-2). A range of doxycycline concentrations were dosed on the cells for 48 hours to test for induction of

Genome-Wide Profiling of Humoral Immune Response to Coxiella burnetii Infection by Protein Microarray

DTIC Science & Technology

2010-01-01

mortality rate for Chronic Q fever to less than 1% [1, 4, 5]. Chronic infections may cause life-threatening endocarditis but may not show apparent...Houpikian, P., Tissot Dupont, H., Riss, J. M. et a/., Treatment of a fever endocarditis : comparison of 2 regimens containing doxycycline and ofloxacin...fever endocarditis . J. Infect. Dis. 1998, 178, 278-281. [7) Yu, X., Raoult, D., Serotyping Coxiella burnetii isolates from acute and chronic a fever

Targeted Therapy Combined with Immune Modulation Using Gold Nanoparticles for Treating Metastatic Colorectal Cancer

DTIC Science & Technology

2017-09-01

collaborator, Dr. Luke Dow. We bred these pairs of mice to create a colony of transgenic mice, and continue to breed them as needed. When experimental...colony of transgenic mice. When experimental mice are 8 weeks of age, they are treated with 4-hydroxytamofixen (4OHT) and put on continuous doxycycline...and human cells and transgenic mouse models. These experiments will determine the effectiveness of this approach and, if successful, will lead to

Doxycycline Inhibits Vascular Leakage and Prevents the Development of Pulmonary Edema

DTIC Science & Technology

2008-12-01

implications. Clin Cancer Res, 12, 917-23. Claffey, K. P., L. F . Brown, L. F . del Aguila, K. Tognazzi, K. T. Yeo, E. J. Manseau, and H. F . Dvorak, 1996...aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice. J Vasc Surg, 35, 923-9. Streit, M., P. Velasco, L. Riccardi ...L. Spencer, L. F . Brown, L. Janes, B. Lange-Asschenfeldt, K. Yano, T. Hawighorst, L. Iruela-Arispe, and M. Detmar, 2000: Thrombospondin-1

[Symptomatic acute Q fever: a series of 87 cases in an area of Mallorca].

PubMed

Raya Cruz, Manuel; Gállego Lezaún, Cristina; García Gasalla, Mercedes; Cifuentes Luna, Carmen; Forteza Forteza, Teodoro; Fernández-Baca, Victoria; Gallegos Álvarez, Carmen; Payeras Cifre, Antonio

2014-04-01

Q fever is a widespread zoonotic infection caused by Coxiella burnetii (C. burnetii). Acute infection varies from a self-limited flu-like illness to pneumonia or hepatitis. A retrospective case study from March 2003 to December 2011 was conducted in the Hospital Son Llàtzer in Palma de Mallorca. Acute Q-fever was diagnosed in a patient with clinical suspicion and IgM in phase ii positive (≥ 1/40), with a positive IgG (≥1/80), or when IgG seroconversion was observed during convalescence. A total of 87 cases of acute Q fever were diagnosed. The median age was 50 years (range 21-89), and 69 (79.3%) were male. Fever and headache were the most common symptoms. Pneumonia was diagnosed in 39 (44.8%) patients, febrile episode in 21 (24.1%), and acute hepatitis in 23 (25.6%). Increased serum transaminases were observed in 19 (21.8%). Doxycycline was prescribed in 29 cases (33.4%). There were 30 (34.5%) patients lost to follow up after hospital discharge. A favorable outcome was observed in all other cases. Only one new case progressed to chronic Q fever. A total of 87 cases of acute Q fever were diagnosed. The median age was 50 years (range 21-89), and 69 (79.3%) were male. Fever and headache were the most common symptoms. Pneumonia was diagnosed in 39 (44.8%) patients, febrile episode in 21 (24.1%), and acute hepatitis in 23 (25.6%). Increased serum transaminases were observed in 19 (21.8%). Doxycycline was prescribed in 29 cases (33.4%). There were 30 (34.5%) patients lost to follow up after hospital discharge. A favorable outcome was observed in all other cases. Only one new case progressed to chronic Q fever. Acute Q fever acute is common our environment. Pneumonia was the most common clinical presentation. Even although doxycycline was prescribed in a small number of patients, a favorable outcome was observed in all cases. Copyright © 2013 Elsevier España, S.L. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Accumulation of antibiotics and heavy metals in meat duck deep litter and their role in persistence of antibiotic-resistant Escherichia coli in different flocks on one duck farm.

PubMed

Lin, Y; Zhao, W; Shi, Z D; Gu, H R; Zhang, X T; Ji, X; Zou, X T; Gong, J S; Yao, W

2017-04-01

Meat duck deep litter is considered to be an ideal environment for the evolution of bacterial antibiotic resistance if it is under poor management. The aim of this study was to characterize the accumulation of antibiotics and heavy metals in the deep litter and their role in the persistence of antibiotic resistance of Escherichia coli, and evaluate the service life of the deep litter. Samples were collected from initial, middle, and final stages of deep litter within 3 barns (zero, 4, and 8 rounds of meat duck fattening, d 34) and 9 flocks, with known consumption of antibiotics in the controlled trail. The feed and litter levels of consumed antibiotics and heavy metals were measured. E. coli (n = 147) was isolated and typed by Eric-PCR and the phylogenetic grouping technique, while minimal inhibitory concentrations of antibiotics and heavy metals were measured. This study confirmed the continuous accumulation of doxycycline and many heavy metals in the deep litter. The population of resistant certain bacteria to doxycycline (16 mg/L, 100 mg/L) or ofloxacin (8 g/mL, 50 g/mL) increased in the used deep litter (rounds 4 and 8). E. coli isolated from the 3 stages of sampling were highly resistant to ampicillin, tetracycline, florfenicol, and doxycycline. Increased resistance to ceftiofur, enrofloxacin, ofloxacin, and gentamicin were seen in the isolates from the final stage of deep litter. In addition, the percentage of isolates tolerant to zinc, copper, and cadmium and the numbers of Group-B2 isolates all increased in the used deep litter, and the isolates of each stage belonged predominantly to commensal groups. The antibiotic resistance of isolates with identical Eric-PCR patterns had improved from round 4 to 8, and differences still existed in the resistance profiles of isolates with identical Eric-PCR patterns from different barns of the same round. This study concluded that deep litter could be suitable for the evolution of bacterial antibiotic

In Vitro Sensitivity and Resistance of 46 Leptospira Strains Isolated from Rats in the Philippines to 14 Antimicrobial Agents▿ †

PubMed Central

Chakraborty, Antara; Miyahara, Satoshi; Villanueva, Sharon Y. A. M.; Gloriani, Nina G.; Yoshida, Shin-ichi

2010-01-01

The in vitro susceptibilities of 46 Leptospira isolates from rats to 14 antimicrobial agents were tested. All of the strains were found to be sensitive to ampicillin, cefotaxime, ciprofloxacin, norfloxacin, doxycycline, erythromycin, and streptomycin. In contrast, the tested isolates showed resistance to amphotericin B, 5-fluorouracil, fosfomycin, trimethoprim, sulfamethoxazole, neomycin, and vancomycin. These findings will help in selecting effective and ineffective antimicrobials for treatment of leptospirosis and for the development of new selective media, respectively. PMID:20855741

Parinaud's oculoglandular syndrome: A case report.

PubMed

Galindo-Bocero, J; Sánchez-García, S; Álvarez-Coronado, M; Rozas-Reyes, P

2017-01-01

A 33-year old woman presents with unilateral granulomatous conjunctivitis, ipsilateral regional lymphadenopathy and fever. A Bartonella henselae infection is demonstrated by indirect immunofluorescence, and a diagnosis of a Parinaud's oculoglandular syndrome is established. Outcome after treatment with oral doxycycline is satisfactory. Parinaud's oculoglandular syndrome is the most frequent ocular manifestation of a Bartonella henselae infection. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

A lentivirus-free inducible CRISPR-Cas9 system for efficient targeting of human genes.

PubMed

Bisht, Kamlesh; Grill, Sherilyn; Graniel, Jacqueline; Nandakumar, Jayakrishnan

2017-08-01

CRISPR-Cas9 is a cutting-edge tool for modifying genomes. The efficacy with which Cas9 recognizes its target has revolutionized the engineering of knockouts. However this efficacy complicates the knocking out of important genes in cultured cells. Unedited cells holding a survival advantage within an edited population can confound the knockout phenotype. Here we develop a HeLa-based system that overcomes this limitation, incorporating several attractive features. First, we use Flp-recombinase to generate clones stably integrated for Cas9 and guide RNAs, eliminating the possibility of unedited cells. Second, Cas9 can be induced uniformly in the clonal cultures using doxycycline to measure the knockout phenotype. Third, two genes can be simultaneously knocked out using this approach. Finally, by not involving lentiviruses, our method is appealing to a broad research audience. Using this methodology we generated an inducible AGO2-knockout cell line showing normal RNA interference in the absence of doxycycline. Upon induction of Cas9, the AGO2 locus was cleaved, the AGO2 protein was depleted, and RNA interference was compromised. In addition to generating inducible knockouts, our technology can be adapted to improve other applications of Cas9, including transcriptional/epigenetic modulation and visualization of cellular DNA loci. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

ACUTE CHOLECYSTITIS AS AN UNUSUAL PRESENTATION OF SCRUB TYPHUS: A REPORT OF TWO CASES AND REVIEW OF THE LITERATURE.

PubMed

Charoenphak, Sirima; Rattanawong, Pattara; Sungkanuparph, Somnuek

2017-01-01

Scrub typhus rarely presents with acute cholecystitis. We present 2 cases of scrub typhus with cholecystitis. The first patient is a 62 year old female who presented to the hospital with fever and body aches for 1 week and right upper quadrant abdominal pain for 3 days. She gave a history of an insect bite 2 weeks previously. She was diagnosed as having acute cholecystitis and underwent cholecystectomy. She continued with fever post-operatively and physical examination revealed an eschar. She had an immunofluorescence assay (IFA) performed that revealed a high IgM titer for Orientia tsutsugamushi. She was diagnosed as having scrub typhus, treated with doxycycline and she recovered completely. The second patient also presented to the hospital with a 1 week history of fever and upper quadrant abdominal pain. She was diagnosed with having cholecystitis. Her symptoms did not improve with intravenous antibiotics and further investigation revealed elevated titers for O. tsutsugamushi and Leptospira interrogans. She was diagnosed as having a co-infection of scrub typhus and leptospirosis and treated with doxycycline. She recovered completely. Patients from scrub typhus endemic regions who present with acute cholecystitis but do not respond to traditional treatment should be tested for scrub typhus and leptospirosis and should have a careful admission physical examination looking for eschar formation, since scrub typhus may present with acute cholecystitis.

Antimicrobial Resistance of Campylobacter Isolates from Retail Meat in the United States between 2002 and 2007▿

PubMed Central

Zhao, S.; Young, S. R.; Tong, E.; Abbott, J. W.; Womack, N.; Friedman, S. L.; McDermott, P. F.

2010-01-01

The emergence of antimicrobial resistance in Campylobacter spp. has been a growing public health concern globally. The objectives of this study were to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Campylobacter spp. recovered by the National Antimicrobial Resistance Monitoring System (NARMS) retail meat program. Retail meat samples (n = 24,566) from 10 U.S. states collected between 2002 and 2007, consisting of 6,138 chicken breast, 6,109 ground turkey, 6,171 ground beef, and 6,148 pork chop samples, were analyzed. A total of 2,258 Campylobacter jejuni, 925 Campylobacter coli, and 7 Campylobacter lari isolates were identified. Chicken breast samples showed the highest contamination rate (49.9%), followed by ground turkey (1.6%), whereas both pork chops and ground beef had <0.5% contamination. The most common resistance was to doxycycline/tetracycline (46.6%), followed by nalidixic acid (18.5%), ciprofloxacin (17.4%), azithromycin and erythromycin (2.8%), telithromycin (2.4%), clindamycin (2.2%), and gentamicin (<0.1%). In a subset of isolates tested, no resistance to meropenem and florfenicol was seen. C. coli isolates showed higher resistance rates to antimicrobials, with the exception of doxycycline/tetracycline, than those seen for C. jejuni. Pulsed-field gel electrophoresis (PFGE) fingerprinting resulted in 1,226 PFGE profiles among the 2,318 isolates, with many clones being widely dispersed throughout the 6-year sampling period. PMID:20971875

Antimicrobial resistance of Campylobacter isolates from retail meat in the United States between 2002 and 2007.

PubMed

Zhao, S; Young, S R; Tong, E; Abbott, J W; Womack, N; Friedman, S L; McDermott, P F

2010-12-01

The emergence of antimicrobial resistance in Campylobacter spp. has been a growing public health concern globally. The objectives of this study were to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Campylobacter spp. recovered by the National Antimicrobial Resistance Monitoring System (NARMS) retail meat program. Retail meat samples (n = 24,566) from 10 U.S. states collected between 2002 and 2007, consisting of 6,138 chicken breast, 6,109 ground turkey, 6,171 ground beef, and 6,148 pork chop samples, were analyzed. A total of 2,258 Campylobacter jejuni, 925 Campylobacter coli, and 7 Campylobacter lari isolates were identified. Chicken breast samples showed the highest contamination rate (49.9%), followed by ground turkey (1.6%), whereas both pork chops and ground beef had <0.5% contamination. The most common resistance was to doxycycline/tetracycline (46.6%), followed by nalidixic acid (18.5%), ciprofloxacin (17.4%), azithromycin and erythromycin (2.8%), telithromycin (2.4%), clindamycin (2.2%), and gentamicin (<0.1%). In a subset of isolates tested, no resistance to meropenem and florfenicol was seen. C. coli isolates showed higher resistance rates to antimicrobials, with the exception of doxycycline/tetracycline, than those seen for C. jejuni. Pulsed-field gel electrophoresis (PFGE) fingerprinting resulted in 1,226 PFGE profiles among the 2,318 isolates, with many clones being widely dispersed throughout the 6-year sampling period.

[Lyme disease--clinical manifestations and treatment].

PubMed

Stock, Ingo

2016-05-01

Lyme disease (Lyme borreliosis) is a systemic infectious disease that can present in a variety of clinical manifestations. The disease is caused by a group of spirochaetes--Borrelia burgdorferi sensu lato or Lyme borrelia--that are transmitted to humans by the bite of Ixodes ticks. Lyme disease is the most common arthropode-borne infectious disease in many European countries including Germany. Early localized infection is typically manifested by an erythema migrans skin lesion, in rarer cases as a borrelial lymphocytoma. The most common early disseminated manifestation is (early) neuroborreliosis. In adults, neuroborreliosis appears typically as meningoradiculoneuritis. Neuroborreliosis in children, however, is typically manifested by meningitis. In addition, multiple erythema migrans lesions and Lyme carditis occur relatively frequently. The most common manifestation oflate Lyme disease is Lyme arthritis. Early manifestations (and usually also late manifestations) of Lyme disease can be treated successfully by application of suitable antibacterial agents. For the treatment of Lyme disease, doxycycline, certain penicillins such as amoxicillin and some cephalosporins (ceftriaxone, cefotaxime, cefuroxime axetil) are recommended in current guidelines. A major challenge is the treatment of chronic, non-specific disorders, i. e., posttreatment Lyme disease syndrome and "chronic Lyme disease". Prevention of Lyme disease is mainly accomplished by protecting against tick bites. Prophylactic administration of doxycycline after tick bites is generally not recommended in Germany. There is no vaccine available for human beings.

Surface properties of sprayed and electrodeposited ZnO rod layers

NASA Astrophysics Data System (ADS)

Gromyko, I.; Krunks, M.; Dedova, T.; Katerski, A.; Klauson, D.; Oja Acik, I.

2017-05-01

Herein we present a comparative study on as-deposited, two-month-stored, and heat-treated ZnO rods obtained by spray pyrolysis (SP) at 550 °C, and electrodeposition (ED) at 80 °C. The aim of the study is to establish the reason for different behaviour of wettability and photocatalytic activity (PA) of SP and ED rods. Samples were studied using XPS, SEM, XRD, Raman, contact angle (CA) measurements and photocatalytic oxidation of doxycycline. Wettability and PA are mainly controlled by surface composition rather than by morphology. The relative amount of hydroxyl groups on the surface of as-deposited ED rods is four times higher compared to as-deposited SP rods. Opposite to SP rods, ED rods contain oxygen vacancy defects (Vo). Therefore, as-deposited ED rods are superhydrophilic (CA ∼ 3°) and show highest PA among studied samples, being three times higher compared to SP rods (removing of 75% of doxycycline after 30 min). It was revealed that as-deposited ED rods are inclined to faster contamination. The amount of Cdbnd C groups on the surface of aged ED rods is six times higher compared to aged SP rods. Stored ED samples become hydrophobic (CA ∼ 120°) and PA decreases sharply while SP rods remain hydrophilic (CA ∼ 50°), being more resistive to the contamination.

Update on the management of rosacea: a status report on the current role and new horizons with topical azelaic acid.

PubMed

Del Rosso, James Q; Kircik, Leon H

2014-12-01

Azelaic acid (AzA) 15% gel has been available in the United States for slightly over a decade, approved for treatment of the inflammatory lesions (papules and pustules) of rosacea. Efficacy and safety have been established in multiple studies both as monotherapy and in combination with oral doxycycline. Azelaic acid 15% gel has been shown not to induce epidermal permeability barrier impairment, and proper skin care reduces the likelihood of neurosensory adverse effects of stinging and burning that can affect a subset of patients with rosacea. Azelaic acid 15% gel appears to produce a quicker onset of clinical effect than metronidazole in some patients when either agent is used in combination with subantimicrobial dose doxycycline; however, both topical agents are effective when used in this combination approach for papulopustular rosacea (PPR). Although more information is needed on the modes of action of AzA in the treatment of rosacea, downregulation of the cathelicidin pathway appears to be one operative mode of action based on in vitro and in vivo studies, including data from patients treated with AzA 15% gel for PPR. Azelaic acid 15% foam is currently in the latter stages of development for PPR, with pivotal studies demonstrating efficacy and favorable tolerability, including a very low incidence of stinging, burning, and itching even without the use of designated skin care products.

Safety of antimalarial medications for use while scuba diving in malaria Endemic Regions.

PubMed

Petersen, Kyle; Regis, David P

2016-01-01

Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is unknown. Of particular concern would be medications with adverse effects that could either mimic diving related illnesses such as barotrauma, decompression sickness (DCS) and gas toxicities, or increase the risk for such illnesses. We conducted a review of PubMed and Cochrane databases to determine rates of neurologic adverse effects or other effects from antimalarials that may be a problem in the diving environment. One case report was found on diving and mefloquine. Multiple case reports and clinical trials were found describing neurologic adverse effects of the major chemoprophylactic medications atovaquone/proguanil, chloroquine, doxycycline, mefloquine, and primaquine. Of the available literature, atovaquone/proguanil and doxycycline are most likely the safest agents and should be preferred; atovaquone/proguanil is superior due to reduced rates of sunburn in the marine environment. Primaquine also appears to be safe, but has reduced efficacy against P. falciparum ; mefloquine possesses the highest rate of neurologic side effects and therefore these agents should be limited to extreme cases of patients intolerant to other agents. Chloroquine appears unsafe in the hyperbaric environment and should be avoided. More studies are required to include database reviews of returned divers traveling to malaria endemic areas and randomized controlled trials in the hyperbaric environments.

[Undulant fever and autoimmune hemolytic anemia in a 20-year-old exchange student from Jordan - the human brucellosis as an important differential diagnosis in migrants].

PubMed

Trawinski, Henning; Gräber, Sandra; Leifels, Michael; Schubert, Stefan; Lübbert, Christoph

2015-12-01

A 20-year-old Jordanian exchange student presents with recurrent fever, night sweats, cough, and swelling and redness around the ankle. Physical examination further reveals bilateral ankle arthritis and painful cervical lymphadenopathy. Laboratory tests show signs of autoimmune hemolytic anemia, elevated liver function tests, and moderate laboratory signs of inflammation. All blood cultures reveal growth of gram-negative coccoid rods which are initially identified by mass spectrometry as Moraxella lacunata and Ochrobactrum anthropi. However, antimicrobial therapy with imipenem / cilastatin does not improve the patient's clinical condition. Based on the travel history including consumption of yogurt from unpasteurized sheep's milk, we perform serological tests with a strongly positive result for Brucella species, and additional work-up of blood culture isolates confirm the definitive diagnosis of brucellosis (Malta fever, infection by Brucella melitensis). After initiation of antimicrobial therapy with doxycycline and rifampin the patient shows complete resolution of fever. Arthritis, autoimmune hemolytic anemia and accompanying hepatitis improve in the course. Thus, since brucellosis is endemic to countries like Jordan, it should be considered as a possible agent of fever of unknown origin especially in migrants unresponsive to empiric therapy and appropriate diagnostic tests including meticulous validation of blood cultures should be performed. Standard therapy is a combination of doxycycline with rifampin for at least 6 weeks. © Georg Thieme Verlag KG Stuttgart · New York.

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras.

PubMed

Podsypanina, Katrina; Politi, Katerina; Beverly, Levi J; Varmus, Harold E

2008-04-01

Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of Kras(G12D) in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and Kras(G12D) transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies.

Enhanced efficacy of sequential administration of Albendazole for the clearance of Wuchereria bancrofti infection: Double blind RCT.

PubMed

De Britto, R L; Vanamail, P; Sankari, T; Vijayalakshmi, G; Das, L K; Pani, S P

2015-06-01

Till today, there is no effective treatment protocol for the complete clearance of Wuchereria bancrofti (W.b) infection that causes secondary lymphoedema. In a double blind randomized control trial (RCT), 146 asymptomatic W. b infected individuals were randomly assigned to one of the four regimens for 12 days, DEC 300 mg + Doxycycline 100 mg coadministration or DEC 300 mg + Albendazole 400 mg co-administration or DEC 300 mg + Albendazole 400 mg sequential administration or control regimen DEC 300 mg and were followed up at 13, 26 and 52 weeks post-treatment for the clearance of infection. At intake, there was no significant variation in mf counts (F(3,137)=0.044; P=0.988) and antigen levels (F(3,137)=1.433; P=0.236) between the regimens. Primary outcome analysis showed that DEC + Albendazole sequential administration has an enhanced efficacy over DEC + Albendazole co-administration (80.6 Vs 64.7%), and this regimen is significantly different when compared to DEC + doxycycline co-administration and control (P<0.05), in clearing microfilaria in 13 weeks. Secondary outcome analysis showed that, all the trial regimens were comparable to control regimen in clearing antigen (F(3, 109)=0.405; P=0.750). Therefore, DEC + Albendazole sequential administration appears to be a better option for rapid clearance of W. b microfilariae in 13 weeks time. (Clinical trials.gov identifier - NCT02005653).