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Tuberculosis (Edinburgh, Scotland) May 2023Multidrug-resistant tuberculosis (MDR-TB) has become a big threaten to global health. The current strategy for treatment of MDR-TB and extensive drug resistant...
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) has become a big threaten to global health. The current strategy for treatment of MDR-TB and extensive drug resistant tuberculosis (XDR-TB) is with low efficacy and high side effect. While new drug is fundamental for cure MDR-TB, repurposing the Food and Drug Administration (FDA)-approved drugs represents an alternative soluation with less cost.
METHODS
The activity of 8 tetracycline-class antibiotics against mycobacterium tuberculosis (M.tb) were determined by Minimum Inhibitory Concentration (MIC) in vitro. A transposon M.smeg libraries was generated by using the Harm phage and then used to isolate the conditional growth mutants in doxycycline containing plate. Eleven mutants were isolated and genomic DNAs were extracted using the cetyltrimethyl ammonium bromide (CTAB) method and analyzed by whole genome sequencing.
RESULTS
We found that three of eight drugs efficiently inhibited mycobacteria growth under the peak plasma concentration in the human body. Further tests showed these three tetracycline analogs (demeclocycline, doxycycline and methacycline) had antimicrobial activity against seven clinical isolates, including MDR and XDR strains. Among them, Doxycycline had the lowest MICs in all mycobacteria strains tested in this study. By using a transposon library, we identify the insertion of transposon in two genes, porin and MshA, associatewith the resistant to doxycycline.
CONCLUSIONS
Our findings show that tetracycline analogs such as doxycycline, has bactericidal activity against not only drug sensitive M.tb, but also clinical MDR and XDR strains, provided proof of concept to repurpose doxycycline to fight MDR-TB and XDR-TB. Further investigations are warranted to clarify the underlying mechanism and optimize the strategy in combination with other anti-TB drugs.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Doxycycline; Tuberculosis, Multidrug-Resistant; Tetracycline; Drug Resistance; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 36963294
DOI: 10.1016/j.tube.2023.102336 -
Cureus Dec 2019Syndrome of inappropriate antidiuretic hormone secretion may be a frequent accompaniment of aging without an obvious central nervous system or pulmonary disorder, tumor,...
Syndrome of inappropriate antidiuretic hormone secretion may be a frequent accompaniment of aging without an obvious central nervous system or pulmonary disorder, tumor, or drugs as the confounding factor. Treatment is often warranted due to complex symptomatology that is often associated with unfavorable clinical outcomes. Although V-receptor antagonists are effective in increasing serum sodium, their side-effect profile and cost may be a barrier to its use. We report a patient with symptomatic, severe, chronic hyponatremia requiring multiple hospitalizations, who was successfully maintained on long-term demeclocycline therapy.
PubMed: 31988816
DOI: 10.7759/cureus.6415 -
BMC Oral Health Jun 2021Pulpal and periodontal healing are two main concerns of delayed replantation of avulsed teeth. The objective of this review was to evaluate the effectiveness of topical...
BACKGROUND
Pulpal and periodontal healing are two main concerns of delayed replantation of avulsed teeth. The objective of this review was to evaluate the effectiveness of topical and systemic application of tetracyclines on pulpal and periodontal healing after tooth replantation.
METHODS
A comprehensive electronic search was conducted in six databases. This systematic review was carried out according to Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
RESULTS
After exclusion of 246 irrelevant papers, 14 animal studies and one human study were included in this review. The human study showed that avulsed permanent teeth treated with doxycycline did not show a better clinical outcome for pulp and periodontal healing compared with treatment with normal saline. As for animal studies, significant more pulpal healing was observed in immature teeth treated with topical doxycycline in two researches, while another one study showed that there is no difference between teeth treated with normal saline and teeth treated with doxycycline. Systemic doxycycline exerted no significant effect on pulpal revascularization illustrated by one research. Only one out of four articles illustrated the positive effect of systemic tetracyclines on periodontal healing. One paper reported that intracanal application of demeclocycline promoted favorable periodontal healing. Two articles showed topical doxycycline contributed to favorable periodontal healing, while five studies showed no significant effect of topical tetracyclines on periodontal healing.
CONCLUSIONS
As a result of data heterogeneity and limitations of the studies, the effect of topical or systemic application of tetracyclines on pulpal and periodontal healing is inconclusive. More studies are required to get more clinically significant conclusions.
Topics: Animals; Dental Pulp; Humans; Periodontal Ligament; Tetracyclines; Tooth Avulsion; Tooth Replantation; Wound Healing
PubMed: 34090399
DOI: 10.1186/s12903-021-01615-y -
International Immunopharmacology Jan 2024Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver...
Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver fibrosis therapy. Since tetracycline antibiotics were recently demonstrated as EphB kinase inhibitors, in present study we investigated their therapeutic potential against liver fibrosis. Our results showed that the tetracycline combination of demeclocycline (D), chlortetracycline (C), and minocycline (M) inhibited the activation of hepatic stellate cells (HSCs) in vitro and alleviated CCl-induced animal model of liver fibrosis in vivo. Mechanistically, DCM combination inhibited EphB1/2 phosphorylation and subsequent activation of the MAPK signaling. Moreover, we found that short-term and low-dose DCM combination treatment decreased tissue inflammation and improved liver fibrosis in mice. Thus, our study indicates that tetracyclines may be repurposed for the treatment of liver fibrosis.
Topics: Animals; Mice; Signal Transduction; Tetracyclines; Tetracycline; Liver Cirrhosis; Anti-Bacterial Agents; Hepatic Stellate Cells; Liver; Carbon Tetrachloride
PubMed: 37992441
DOI: 10.1016/j.intimp.2023.111261 -
Life Sciences Sep 2020The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted...
The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (M). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 M crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 M. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 M which can used in combinational therapy against SARS-CoV-2 infection.
Topics: Anti-Bacterial Agents; Antiviral Agents; Betacoronavirus; Binding Sites; COVID-19; Computational Biology; Coronavirus Infections; Databases, Genetic; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Peptide Hydrolases; Pneumonia, Viral; Protease Inhibitors; Protein Binding; SARS-CoV-2; Tetracyclines; Viral Nonstructural Proteins
PubMed: 32653520
DOI: 10.1016/j.lfs.2020.118080 -
European Endodontic Journal Oct 2022To explore the long-term effects on discolouration by demeclocycline HCl (Ledermix, LED) or doxycycline hyclate (Doxymix, DOX) pastes placed in extracted human teeth...
OBJECTIVE
To explore the long-term effects on discolouration by demeclocycline HCl (Ledermix, LED) or doxycycline hyclate (Doxymix, DOX) pastes placed in extracted human teeth over a 27-month period under different storage conditions.
METHODS
The canals in 38 teeth were prepared carefully, to minimize exposure to contamination from irrigants, then either LED (Lederle Pharmaceuticals, Germany) or DOX (Ozdent, Australia) were placed. Samples were stored in the dark for 3 months followed by daylight for 24 months. The storage conditions varied as follows: Group 1: Open access, dry storage (OD); Group 2: Closed access, dry storage (CD); Group 3: Open access, wet storage (OW); Group 4: Closed access, wet storage (n=4 for each material). Additional teeth were used as controls: Polyethylene glycol only in a closed canal; and saline only irrigation with LED paste in a closed canal. Standardised digital photographs were taken over 27 months and evaluated for changes in luminosity.
RESULTS
Darkening of tooth structure occurred in all LED groups and in the two DOX groups that were stored wet, during exposure to light, with a faster rate with LED. The most rapid staining occurred with LED in moist conditions with an open access cavity. The least staining occurred with DOX in samples stored dry. With prolonged exposure to light, a reversal in staining occurred with DOX at 3 months and LED at 9 months.
CONCLUSION
Staining of tooth structure is influenced by the choice of medicament, and by exposure to moisture and air. Light has a bimodal effect, first driving staining, but later reversing it. This can be explained by different wavelengths of light causing photodegradation and photo-oxidation of tetracyclines and their complexes with tooth mineral.
Topics: Demeclocycline; Doxycycline; Drug Combinations; Humans; Polyethylene Glycols; Root Canal Irrigants; Tetracyclines; Triamcinolone Acetonide
PubMed: 36217644
DOI: 10.14744/eej.2022.07108 -
Cureus Apr 2022Hyponatraemia is the most common electrolyte abnormality encountered in the inpatient setting and is associated with increased morbidity, mortality, and length of...
Hyponatraemia is the most common electrolyte abnormality encountered in the inpatient setting and is associated with increased morbidity, mortality, and length of hospital stay. Syndrome of inappropriate anti-diuresis (SIAD) remains the most common cause. Hyponatraemia due to SIAD presents various challenges in treatment approaches, including poor concordance (e.g., to fluid restriction), medication intolerance (e.g., demeclocycline), and risk of rapid sodium shifts (e.g., with vaptan therapy). The use of oral sodium chloride (NaCl) tablets is a recognised treatment approach. However, it is not commonly advocated. We present the cases of two elderly patients in whom the temporary use of NaCl tablets, as an adjunct to fluid restriction, led to safe and effective correction of SIAD-related hyponatraemia with resultant reduced length of hospital admission.
PubMed: 35475246
DOI: 10.7759/cureus.24367 -
Frontiers in Pediatrics 2021Suprasellar arachnoid cysts represent a rare occurrence in the pediatric population and usually cause symptoms related to mass effect and can occasionally cause...
Suprasellar arachnoid cysts represent a rare occurrence in the pediatric population and usually cause symptoms related to mass effect and can occasionally cause endocrine dysfunctions. The association between SAC and the syndrome of inappropriate antidiuretic hormone (SIADH) in the pediatric population has rarely been described previously. In most cases, SIADH is temporary and resolves by treating the underlying cause. The first-line treatment consists of fluid restriction in asymptomatic children. Oral urea and demeclocycline are other effective treatment options. Vaptans are a new class of medication for the management of SIADH. These agents are a nonpeptide vasopressin V2 receptor antagonist that selectively antagonizes the antidiuretic effect of AVP, resulting in excretion of diluted urine or "aquaresis." Their efficacy has been shown in adult patients with euvolemic or hypervolemic hyponatremia. However, evidence is lacking in pediatric patients with SIADH. We report the case of a 9-year-old female child with a SAC, who underwent endoscopic fenestration at the age of 2 years. After surgery she developed chronic hyponatremia due to SIADH. Hyponatremia was refractory to treatment with fluid restriction, oral sodium, and urea. In order to normalize serum sodium levels, tolvaptan treatment was started on a compassionate-use basis; 24-48 h later serum sodium levels returned to normal. To date, tolvaptan has been used regularly for 6 years with no side effects occurring during the treatment period. This is the first case of a child with chronic SIADH secondary to SAC successfully treated with tolvaptan. Further studies are needed to demonstrate its usefulness on a broader case series.
PubMed: 34336740
DOI: 10.3389/fped.2021.684131 -
Food Frontiers Jun 2020Angiotensin converting enzyme 2 (ACE2) and main protease (M) are significant target proteins, mainly involved in the attachment of viral genome to host cells and aid in...
Angiotensin converting enzyme 2 (ACE2) and main protease (M) are significant target proteins, mainly involved in the attachment of viral genome to host cells and aid in replication of severe acute respiratory syndrome-coronaviruses or SARS-CoV genome. In the present study, we identified 11 potent bioactive compounds from ethanolic leaf extract of (L.) by using GC-MS analysis. These potential bioactive compounds were considered for molecular docking studies against ACE2 and M target proteins to determine the antiviral effects against SARS-COV. Results exhibits that among 11 compounds from (L.), urso-deoxycholic acid, demeclocycline, tetracycline, chlorotetracycline, and ethyl iso-allocholate had potential viral inhibitory activity. Hence, the present findings suggested that chemical constitution present in (L.) will address inhibition of corona viral replication in host cells.
PubMed: 32838301
DOI: 10.1002/fft2.29 -
ADMET & DMPK 2020The bioavailability of tetracyclines is markedly decreased when co-administered with antacids, milk, or food containing Ca. Previously, it was suggested that the...
The bioavailability of tetracyclines is markedly decreased when co-administered with antacids, milk, or food containing Ca. Previously, it was suggested that the effective intestinal permeation of tetracycline (TC) was decreased due to Ca linked mucin binding in the mucosal side. In the present study, we investigated the effect of Ca, Mg, and mucin on the membrane permeation of six tetracyclines (TC, oxytetracycline (OTC), minocycline (MINO), doxycycline (DOXY), demeclocycline (DMCTC), and chlortetracycline (CTC)). The membrane permeability values (P) of tetracyclines were measured by the parallel artificial membrane permeation assay (PAMPA) using soybean lecithin - decane (SL-PAMPA) and octanol (OCT-PAMPA) membranes. In SL-PAMPA, Ca markedly decreased the P values of all tetracyclines. In OCT-PAMPA, Ca increased the P values of TC, CTC, and DMCTC, but not DOXY, OTC, and MINO. Mg decreased the P values of all tetracyclines in both SL-PAMPA and OCT-PAMPA (except for CTC in OCT-PAMPA). The addition of mucin had little or no effect in all cases. In contrast to the previously suggested mechanism, the results of the present study suggested that Ca chelate formation decreased the membrane permeation of tetracyclines, irrespective of Ca linked mucin binding. Molecular speciation analysis suggested that the permeation of TC - metal chelates was negligibly small in SL-PAMPA.
PubMed: 35300369
DOI: 10.5599/admet.797