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Frontiers in Cellular and Infection... 2021Boromycin is a boron-containing macrolide antibiotic produced by with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most...
Boromycin is a boron-containing macrolide antibiotic produced by with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most antimalarial antibiotics affect plasmodial organelles of prokaryotic origin and have a relatively slow onset of action. They are used for malaria prophylaxis and for the treatment of malaria when combined to a fast-acting drug. Despite the success of artemisinin combination therapies, the current gold standard treatment, new alternatives are constantly needed due to the ability of malaria parasites to become resistant to almost all drugs that are in heavy clinical use. antiplasmodial activity screens of tetracyclines (omadacycline, sarecycline, methacycline, demeclocycline, lymecycline, meclocycline), macrolides (oleandomycin, boromycin, josamycin, troleandomycin), and control drugs (chloroquine, clindamycin, doxycycline, minocycline, eravacycline) revealed boromycin as highly potent against and the zoonotic . In contrast to tetracyclines, boromycin rapidly killed asexual stages of both species already at low concentrations (~ 1 nM) including multidrug resistant strains (Dd2, K1, 7G8). In addition, boromycin was active against stage V gametocytes at a low nanomolar range (IC: 8.5 ± 3.6 nM). Assessment of the mode of action excluded the apicoplast as the main target. Although there was an ionophoric activity on potassium channels, the effect was too low to explain the drug´s antiplasmodial activity. Boromycin is a promising antimalarial candidate with activity against multiple life cycle stages of the parasite.
Topics: Animals; Anti-Bacterial Agents; Antimalarials; Borates; Malaria, Falciparum; Plasmodium falciparum
PubMed: 35096650
DOI: 10.3389/fcimb.2021.802294 -
ACS Chemical Neuroscience Feb 2023H,N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically...
H,N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically disordered monomeric α-Synuclein (aSyn). We report how solution pH can impact the interpretation of aSyn HSQC NMR spectra and demonstrate that small-molecule formulations (e.g., complexation with acidic salts) can lower sample pH and confound interpretation of drug binding and concomitant protein structural changes. Through stringent pH control, we confirm that several previously identified compounds (EGCG, Baicalin, and Dopamine (DOPA)) as well as a series of potent small-molecule inhibitors of aSyn pathology (Demeclocycline, Ro90-7501, and (±)-Bay K 8644) are capable of direct target engagement of aSyn. Previously, DOPA-aSyn interactions have been shown to elicit a dramatic chemical shift perturbation (CSP) localized to aSyn's H50 at low DOPA concentrations then expanding to aSyn's acidic C-terminal residues at increasing DOPA levels. Interestingly, this CSP profile mirrors our pH titration, where a small reduction in pH affects H50 CSP, and large pH changes induce robust C-terminal CSP. In contrast, under tightly controlled pH 5.0, DOPA induces significant CSPs observed at both ionizable and nonionizable residues. These results suggest that previous interpretations of DOPA-aSyn interactions were conflated with pH-induced CSP, highlighting the need for stringent pH control to minimize potential false-positive interpretations of ligand interactions in HSQC NMR experiments. Furthermore, DOPA's preferential interaction with aSyn under acidic pH represents a novel understanding of DOPA-aSyn interactions that may provide insight into the potential gain of toxic function of aSyn misfolding in α-synucleinopathies.
Topics: alpha-Synuclein; Dihydroxyphenylalanine; Hydrogen-Ion Concentration; Nuclear Magnetic Resonance, Biomolecular; Small Molecule Libraries
PubMed: 36749138
DOI: 10.1021/acschemneuro.2c00782 -
Journal of Experimental Orthopaedics Jul 2024Establishing zonal tendon-to-bone attachment could accelerate the anterior cruciate ligament reconstruction (ACLR) rehabilitation schedule and facilitate an earlier...
PURPOSE
Establishing zonal tendon-to-bone attachment could accelerate the anterior cruciate ligament reconstruction (ACLR) rehabilitation schedule and facilitate an earlier return to sports. KI24RGDS is a self-assembling peptide hydrogel scaffold (SAPS) with the RGDS amino acid sequence. This study aimed to elucidate the therapeutic potential of KI24RGDS in facilitating zonal tendon-to-bone attachment after ACLR.
METHODS
Sixty-four C57BL/6 mice were divided into the ACLR + SAPS and ACLR groups. ACLR was performed using the tail tendon. To assess the maturation of tendon-to-bone attachment, we quantified the area of mineralized fibrocartilage (MFC) in the tendon graft with demeclocycline. Immunofluorescence staining of α-smooth muscle actin (α-SMA) was performed to evaluate progenitor cell proliferation. The strength of tendon-to-bone attachment was evaluated using a pull-out test.
RESULTS
The MFC and maximum failure load in the ACLR + SAPS group were remarkably higher than in the ACLR group on Day 14. However, no significant difference was observed between the two groups on Day 28. The number of α-SMA-positive cells in the tendon graft was highest on Day 7 after ACLR in both the groups and was significantly higher in the ACLR + SAPS group than in the ACLR group.
CONCLUSION
This study highlighted the latent healing potential of KI24RGDS in facilitating early-stage zonal attachment of tendon grafts and bone tunnels post-ACLR. These findings may expedite rehabilitation protocols and shorten the timeline for returning to sports.
LEVEL OF EVIDENCE
Not applicable.
PubMed: 38899049
DOI: 10.1002/jeo2.12061 -
Journal of Clinical Research in... Sep 2017Hyponatremia is the most common electrolyte disorder among hospitalized patients and it is sometimes considered as a poor outcome predictor. Its correction is thus... (Review)
Review
Hyponatremia is the most common electrolyte disorder among hospitalized patients and it is sometimes considered as a poor outcome predictor. Its correction is thus indicated, even in asymptomatic patients. The conventional treatment consists of fluid restriction in presence of euvolemia or hypervolemia; loop diuretics are used in some hypervolemic conditions such as cardiac heart failure, liver cirrhosis and nephrotic syndrome, while intravenous isotonic or hypertonic solutions are administered in hypovolemic conditions. The utilization of demeclocycline and urea is not indicated in pediatric ages due to lack of data on their toxicity and poor tolerance. Recently, a new therapeutic option has been developed, a class of non-peptide arginine vasopressin receptor antagonists called vaptans. Tolvaptan is the only such agent approved in Europe for the treatment of hyponatremia caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH) in adults. In USA, tolvaptan and conivaptan have been approved for treatment of euvolemic and hypervolemic hyponatremia. Few data are so far available in paediatric patients, since only one trial has been registered in Europe which includes children and adolescents, but this trial is still ongoing. Here, we report three children with chronic hyponatremia due to SIADH in which tolvaptan has been used successfully.
Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Child; Child, Preschool; Female; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Tolvaptan
PubMed: 28515029
DOI: 10.4274/jcrpe.4531 -
JBMR Plus Jul 2019Hypercalcemia most often results from primary hyperparathyroidism and malignancy. Adynamic bone disease (ABD) is a form of renal osteodystrophy characterized by reduced...
Hypercalcemia most often results from primary hyperparathyroidism and malignancy. Adynamic bone disease (ABD) is a form of renal osteodystrophy characterized by reduced bone turnover, which can limit the ability of bone to release or store calcium, potentially leading to low, normal, or high serum calcium levels. We describe a 51-year-old dialysis-dependent female with hypercalcemia after parathyroidectomy. A demeclocycline-labeled bone biopsy confirmed adynamic bone disease. Teriparatide, a recombinant form of parathyroid hormone (PTH) used to treat postmenopausal osteoporosis, was prescribed for 12 months and normalized serum calcium levels. Although previous case reports and series have described favorable changes in spine bone mineral density when teriparatide was prescribed for ABD, ours is the first documented case in which teriparatide resolved hypercalcemia due to ABD. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
PubMed: 31372586
DOI: 10.1002/jbm4.10176 -
Drug Testing and Analysis Jul 2022Oxytetracycline is a broad-spectrum antibiotic, which inhibits protein synthesis and is generally used for the treatment of pneumonia, shipping fever, leptospirosis and...
Oxytetracycline is a broad-spectrum antibiotic, which inhibits protein synthesis and is generally used for the treatment of pneumonia, shipping fever, leptospirosis and wound infections in cattle and swine. The present work proposes a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for oxytetracycline quantification in bull plasma, seminal plasma and urine, requiring limited sample treatment before analysis. Extraction with trichloroacetic acid followed by dilution of the supernatant in mobile phase proved to be effective in all three matrices, allowing to rapidly process large batches of samples. Sharp and symmetrical peak shape was obtained using a BEH C18 reversed-phase column in a chromatographic run of just 3.5 min. The mass spectrometer operated in positive electrospray ionization mode and monitored specific transitions for oxytetracycline (461.1 → 425.8) and the internal standard demeclocycline (465.0 → 447.6). The method was validated over concentration ranges suitable for field concentrations of oxytetracycline found in each matrix, showing good linearity during each day of testing (R always >0.99), as also confirmed by analysis of variance (ANOVA) and lack-of-fit tests. Excellent accuracy and precision were demonstrated by calculated bias always within ±15% and CV% below 10% at all quality control (QC) levels in the three matrices. Matrix effect and recovery were investigated for both analytes, which showed consistent and comparable behaviour in each matrix. To our knowledge, this is the first validated approach for mass spectrometric determination of oxytetracycline in seminal plasma and urine. The method was successfully applied to samples collected during a pharmacokinetic study in bulls, allowing to assess the oxytetracycline concentration-time profile in plasma, seminal plasma and urine.
Topics: Animals; Anti-Bacterial Agents; Cattle; Chromatography, High Pressure Liquid; Chromatography, Liquid; Male; Oxytetracycline; Reproducibility of Results; Semen; Spectrometry, Mass, Electrospray Ionization; Swine; Tandem Mass Spectrometry
PubMed: 35195370
DOI: 10.1002/dta.3246 -
Journal of Bone and Joint Infection 2020is gaining recognition as a leading pathogen after orthopaedic shoulder procedures. Photodynamic therapy, a combination of light and a photosensitizer, has...
is gaining recognition as a leading pathogen after orthopaedic shoulder procedures. Photodynamic therapy, a combination of light and a photosensitizer, has demonstrated antimicrobial activity against in the treatment of acne vulgaris. We sought to evaluate the effect of photodynamic therapy using blue light and photosensitizers on isolates from shoulder prosthetic joint infections. strains isolated from 19 patients with shoulder PJI were exposed to blue light alone (415 nm) or in combination with photosensitizers (fluorescein, riboflavin and demeclocycline). strains were divided into 4 categories: , to blue light. 13 of 19 strains (68% were or to blue light alone. Of these 19 strains tested, 11 were tested with blue light and fluorescein or blue light plus riboflavin. Fluorescein (1 µg/mL) enhanced the effect of blue light in 6 of 11 strains (55%). Blue light plus riboflavin (10 µg/mL) resulted enhanced killing in 3 of 11 strains (27%), but produced a paradoxical photoprotective effect in 4 of 11 strains (36%), resulting in a net decrease compared to blue light alone. Demeclocycline, however, enhanced the effect of blue light in 16 of 17 strains (94 %). Blue light with the addition of photosensitizers killed from periprosthetic shoulder infections , with demeclocycline having the most pronounced effect.
PubMed: 32670773
DOI: 10.7150/jbji.46199 -
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