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Antimicrobial Agents and Chemotherapy Apr 2020Doxycycline, an FDA-approved tetracycline, is used in tuberculosis models for the temporal control of mycobacterial gene expression. In these models, animals are...
Doxycycline, an FDA-approved tetracycline, is used in tuberculosis models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant carrying genes of interest under transcriptional control of the doxycycline-responsive TetR- unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of target genes Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of promoters in infected tissues of mice and rabbits.
Topics: Animal Feed; Animals; Anti-Bacterial Agents; Biological Availability; Calcium; Disease Models, Animal; Doxycycline; Female; Gene Silencing; Lung; Mice; Mycobacterium tuberculosis; Rabbits; Tetracycline Resistance; Tissue Distribution; Transgenes; Tuberculosis
PubMed: 32041718
DOI: 10.1128/AAC.02479-19 -
Malaria Journal Apr 2017Anti-malarial drug resistance to chloroquine and sulfadoxine-pyrimethamine has spread from Southeast Asia to Africa. Furthermore, the recent emergence of resistance to... (Review)
Review
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.
Topics: Antimalarials; Chemoprevention; Child; Child, Preschool; Dental Enamel Hypoplasia; Doxycycline; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Infant, Newborn; Malaria
PubMed: 28407772
DOI: 10.1186/s12936-017-1797-9 -
Oncotarget Mar 2017Doxycycline have been reported to exert anti-cancer activity and have been assessed as anti-cancer agents in clinical trials. However, the direct targets of doxycycline...
Doxycycline have been reported to exert anti-cancer activity and have been assessed as anti-cancer agents in clinical trials. However, the direct targets of doxycycline in cancer cells remain unclear. In this study, we used a chemical proteomics approach to identify the Protease-activated receptor 1 (PAR1) as a specific target of inhibition of doxycycline. Binding assays and single-molecule imaging assays were performed to confirm the inhibition of doxycycline to PAR1. The effect of doxycycline on multi-omics and cell functions were assessed based on a PAR1/thrombin model. Molecular docking and molecular dynamic simulations revealed that doxycycline interacts with key amino acids in PAR1. Mutation of PAR1 further confirmed the computation-based results. Moreover, doxycycline provides highly selective inhibition of PAR1 signaling in tumors in vitro and in vivo. Using pathological clinical samples co-stained for doxycycline and PAR1, it was found that doxycycline fluorescence intensity and PAR1 expression shown a clear positive correlation. Thus, doxycycline may be a useful targeted anti-cancer drug that should be further investigated in clinical trials.
Topics: A549 Cells; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Line, Tumor; Disease Progression; Doxycycline; Drug Screening Assays, Antitumor; Female; HCT116 Cells; HEK293 Cells; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Dynamics Simulation; Molecular Targeted Therapy; Random Allocation; Receptor, PAR-1; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 28187433
DOI: 10.18632/oncotarget.15166 -
Proceedings of the National Academy of... Oct 2023Antibiotics, by definition, reduce bacterial growth rates in optimal culture conditions; however, the real-world environments bacteria inhabit see rapid growth...
Antibiotics, by definition, reduce bacterial growth rates in optimal culture conditions; however, the real-world environments bacteria inhabit see rapid growth punctuated by periods of low nutrient availability. How antibiotics mediate population decline during these periods is poorly understood. Bacteria cannot optimize for all environmental conditions because a growth-longevity tradeoff predicts faster growth results in faster population decline, and since bacteriostatic antibiotics slow growth, they should also mediate longevity. We quantify how antibiotics, their targets, and resistance mechanisms influence longevity using populations of and, as the tradeoff predicts, populations are maintained for longer if they encounter ribosome-binding antibiotics doxycycline and erythromycin, a finding that is not observed using antibiotics with alternative cellular targets. This tradeoff also predicts resistance mechanisms that increase growth rates during antibiotic treatment could be detrimental during nutrient stresses, and indeed, we find resistance by ribosomal protection removes benefits to longevity provided by doxycycline. We therefore liken ribosomal protection to a "Trojan horse" because it provides protection from an antibiotic but, during nutrient stresses, it promotes the demise of the bacteria. Seeking mechanisms to support these observations, we show doxycycline promotes efficient metabolism and reduces the concentration of reactive oxygen species. Seeking generality, we sought another mechanism that affects longevity and we found the number of doxycycline targets, namely, the ribosomal RNA operons, mediates growth and longevity even without antibiotics. We conclude that slow growth, as observed during antibiotic treatment, can help bacteria overcome later periods of nutrient stress.
Topics: Anti-Bacterial Agents; Bacteria; Doxycycline; Escherichia coli; Ribosomes; Humans
PubMed: 37751555
DOI: 10.1073/pnas.2221507120 -
Health Technology Assessment... Dec 2023Hidradenitis suppurativa is a chronic inflammatory skin disease characterised by recurrent inflammatory lesions and skin tunnels in flexural sites such as the axilla.... (Observational Study)
Observational Study
BACKGROUND
Hidradenitis suppurativa is a chronic inflammatory skin disease characterised by recurrent inflammatory lesions and skin tunnels in flexural sites such as the axilla. Deroofing of skin tunnels and laser treatment are standard hidradenitis suppurativa interventions in some countries but not yet introduced in the United Kingdom.
OBJECTIVE
To understand current hidradenitis suppurativa management pathways and what influences treatment choices to inform the design of future randomised controlled trials.
DESIGN
Prospective 12-month observational cohort study, including five treatment options, with nested qualitative interviews and an end-of-study consensus workshop.
SETTING
Ten United Kingdom hospitals with recruitment led by dermatology and plastic surgery departments.
PARTICIPANTS
Adults with active hidradenitis suppurativa of any severity not adequately controlled by current treatment.
INTERVENTIONS
Oral doxycycline 200 mg once daily; oral clindamycin and rifampicin, both 300 mg twice daily for 10 weeks initially; laser treatment targeting the hair follicle (neodymium-doped yttrium aluminium garnet or alexandrite); deroofing; and conventional surgery.
MAIN OUTCOME MEASURES
Primary outcome was the proportion of participants who are eligible, and hypothetically willing, to use the different treatment options. Secondary outcomes included proportion of participants choosing each of the study interventions, with reasons for their choices; proportion of participants who switched treatments; treatment fidelity; loss to follow-up rates over 12 months; and efficacy outcome estimates to inform outcome measure instrument responsiveness.
RESULTS
Between February 2020 and July 2021, 151 participants were recruited, with two pauses due to the COVID-19 pandemic. Follow-up rates were 89% and 83% after 3 and 6 months, decreasing to 70% and 44% at 9 and 12 months, respectively, because pandemic recruitment delays prevented all participants reaching their final review. Baseline demographics included an average age of 36 years, 81% female, 20% black, Asian or Caribbean, 64% current or ex-smokers and 86% with a raised body mass index. Some 69% had moderate disease, 19% severe disease and 13% mild disease. Regarding the study's primary outcome, laser treatment was the intervention with the highest proportion (69%) of participants who were eligible and hypothetically willing to receive treatment, followed by deroofing (58%), conventional surgery (54%), the combination of oral clindamycin and rifampicin (44%) and doxycycline (37%). Considering participant willingness in isolation, laser was ranked first choice by the greatest proportion (41%) of participants. The cohort study and qualitative study demonstrated that participant willingness to receive treatment was strongly influenced by their clinician. Fidelity to oral doxycycline was only 52% after 3 months due to lack of effectiveness, participant preference and adverse effects. Delays receiving procedural interventions were common, with only 43% and 26% of participants commencing laser therapy and deroofing, respectively, after 3 months. Treatment switching was uncommon and there were no serious adverse events. Daily pain score text messages were initiated in 110 participants. Daily responses reduced over time with greatest concordance during the first 14 days.
LIMITATIONS
It was not possible to characterise conventional surgery due to a low number of participants.
CONCLUSION
The Treatment of Hidradenitis Suppurativa Evaluation Study established deroofing and laser treatment for hidradenitis suppurativa in the United Kingdom and developed a network of 10 sites for subsequent hidradenitis suppurativa randomised controlled trials.
FUTURE WORK
The consensus workshop prioritised laser treatment and deroofing as interventions for future randomised controlled trials, in some cases combined with drug treatment.
TRIAL REGISTRATION
This trial is registered as ISRCTN69985145.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/35/64) and is published in full in ; Vol. 27, No. 30. See the NIHR Funding and Awards website for further award information.
Topics: Adult; Humans; Female; Male; Doxycycline; Clindamycin; Prospective Studies; Rifampin; Hidradenitis Suppurativa; Cohort Studies; Pandemics; Cost-Benefit Analysis; Randomized Controlled Trials as Topic
PubMed: 38149635
DOI: 10.3310/HWNM2189 -
Journal of Primary Care & Community... 2023Brucellosis is the second most widely spread zoonotic disease. There is less literature on this disease in Pakistan, leading to delayed diagnosis, or the patient remains...
BACKGROUND
Brucellosis is the second most widely spread zoonotic disease. There is less literature on this disease in Pakistan, leading to delayed diagnosis, or the patient remains undiagnosed. This study aims to contribute to Pediatric brucellosis literature, epidemiological, clinical features, laboratory findings, and treatment.
CASE PRESENTATION
We present an 11-year-old child who was admitted to the hospital due to abdominal pain for one month and a fever for 15 days. On abdominal ultrasound, she had hepato-splenomegaly with minimal pleural effusion. A comprehensive diagnostic workup for infectious and immunologic disorders confirmed brucellosis with the antibody tests report. She received doxycycline, rifampin, and trimethoprim-sulfamethoxazole for three months. The treatment was continued with Syrup Doxycycline (50 mg/5 ml), and Syrup Rifampicin (2 g/100 ml) was prescribed for five weeks. Her symptoms were improved by the end of the treatment.
CONCLUSION
is an intracellular pathogen affecting multi-systems of the human body; thus, the treatment is started with antimicrobials that have penetrative effects on a cell. The treatment can be adjusted based on the age group and the complication of the symptoms.
Topics: Female; Humans; Child; Doxycycline; Brucellosis; Rifampin; Trimethoprim, Sulfamethoxazole Drug Combination; Fever; Anti-Bacterial Agents
PubMed: 37148217
DOI: 10.1177/21501319231170497 -
Journal of Infection and Public Health May 2022An unprecedented global health crisis has developed due to the emergence of the mysterious coronavirus-2 of the severe acute respiratory syndrome, which has resulted in... (Review)
Review
An unprecedented global health crisis has developed due to the emergence of the mysterious coronavirus-2 of the severe acute respiratory syndrome, which has resulted in millions of deaths around the globe, as no therapy could control the 'cytokine storm'. Consequently, many vaccines have been developed and several others are being developed for this infection. Although most of the approved vaccines have been highly effective, many developing, and economically poor countries are still deprived of vaccination against SARS-CoV-2 due to the unequal distribution of vaccines worldwide. Furthermore, the uncertainty about the effectiveness of the available vaccines against the emerging mutants and variants also remains a matter of concern. Due to the multistep pathogenesis and unique features, combination therapy using safe immunomodulatory and antiviral drugs should be considered as the most effective and acceptable therapeutic regimen for this infection. Based on a thorough assessment of the literature, it was determined that it would be interesting to study the therapeutic potential of ivermectin and doxycycline, given their roles in several biological pathways involved in SARS CoV-2 pathogenesis. Following that, a comprehensive literature search was undertaken using Scopus, Web of Science, and Pubmed, depending on the inclusion and exclusion criteria. The present study provides a mechanism and comprehensive report, highlighting the role of combined therapy with ivermectin and doxycycline in alleviating the 'cytokine storm' of COVID-19 infection.
Topics: COVID-19; Cytokine Release Syndrome; Doxycycline; Humans; Ivermectin; SARS-CoV-2; Vaccination
PubMed: 35462191
DOI: 10.1016/j.jiph.2022.03.014 -
Lakartidningen Nov 2017
Topics: Bile; Child; Child, Preschool; Doxycycline; Humans; Staining and Labeling; Sweden
PubMed: 29292907
DOI: No ID Found -
PLoS Neglected Tropical Diseases Oct 2023Onchocerciasis is a neglected tropical disease with 217.5 million people globally at risk of having the infection. In both settled and semi-nomadic communities of...
BACKGROUND
Onchocerciasis is a neglected tropical disease with 217.5 million people globally at risk of having the infection. In both settled and semi-nomadic communities of Massangam Health District in Cameroon, Sightsavers has been carrying out test-and-treat with doxycycline and twice-yearly ivermectin distribution. This paper focuses on the cost of test-and-treat with doxycycline in the two community contexts of settled and semi-nomadic.
METHODS
For the valuation, a combination of gross or micro-costing was used to identify cost components, as well as bottom-up and top-down approaches. The opportunity costs of vehicle and equipment use were estimated and included. Not included, however, were the opportunity costs of building use and Ministry of Public Health staff salaries. We only captured the incremental costs of implementing test-and-treat activities as part of a functional annual community-directed treatment with the ivermectin programme.
RESULTS
We estimate the economic cost per person tested and cost per person treated in Massangam to be US$135 and US$667 respectively. Total implementation cost in the settled community was US$79,409, and in the semi-nomadic community US$69,957. Overall, the total economic cost of implementing the doxycycline test-and-treat strategy for onchocerciasis elimination in Massangam came to US$168,345. Financial costs represented 91% of total costs.
CONCLUSIONS
Unit costs of test-and-treat in both settled and semi-nomadic communities are higher than unit costs of community-directed treatment with ivermectin. However, it is critical to note that a two-year implementation shows a significantly larger reduction in infection prevalence than the preceding 20 years of annual community-directed treatment with ivermectin. Test-and-treat with doxycycline may be a cost-effective intervention in places where the prevalence of microfilaria is still high, or in hard-to-reach areas where community-directed treatment with ivermectin and MDA coverage are not high enough to stop transmission or where marginalised populations consistently miss treatment.
Topics: Humans; Onchocerciasis; Ivermectin; Doxycycline; Cameroon; Public Health
PubMed: 37851655
DOI: 10.1371/journal.pntd.0011670 -
Skin Pharmacology and Physiology 2017One of the most important dermatologic side effects of doxycycline is photosensitivity. As doxycycline is important for malaria prophylaxis and malaria is mainly spread... (Review)
Review
BACKGROUND
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.
METHODS
This review is based on a systematic search in PubMed for articles in English and German and a manual search between 1990 and 2015.
RESULTS
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.
CONCLUSION
Evidence base must be improved for giving advice on appropriate prevention measures to travelers taking doxycycline and having a risk of significant sun exposure.
Topics: Anti-Bacterial Agents; Doxycycline; Humans; Malaria; Onycholysis; Photosensitivity Disorders; Sunlight; Ultraviolet Rays
PubMed: 28291967
DOI: 10.1159/000458761