Repurposing of Tetracyclines for COVID-19 Neurological and Neuropsychiatric Manifestations: A Valid Option to Control SARS-CoV-2-Associated Neuroinflammation?

The recent outbreak of coronavirus disease 2019 (COVID-19) has gained considerable attention worldwide due to its increased potential to spread and infect the general population. COVID-19 primarily targets the human respiratory epithelium but also has neuro-invasive potential. Indeed, neuropsychiatric manifestations, such as fatigue, febrile seizures, psychiatric symptoms, and delirium, are consistently observed in COVID-19. The neurobiological basis of neuropsychiatric COVID-19 symptoms is not fully understood. However, previous evidence about systemic viral infections pointed to an ongoing neuroinflammatory response to viral antigens and proinflammatory mediators/immune cells from the periphery. Microglia cells mediate the overproduction of inflammatory cytokines, free radicals, and damage signals, culminating with neurotoxic consequences. Semi-synthetic second-generation tetracyclines, including minocycline (MINO) and doxycycline (DOXY), are safe bacteriostatic agents that have remarkable neuroprotective and anti-inflammatory properties. Promising results have been obtained in clinical trials using tetracyclines for major psychiatric disorders, such as schizophrenia and major depression. Tetracyclines can inhibit microglial reactivity and neuroinflammation by inhibiting nuclear factor kappa B (NF-kB) signaling, cyclooxygenase 2, and matrix metalloproteinases (MMPs). This drug class also has a broad profile of activity against bacteria associated with community-based pneumonia, including atypical agents. COVID-19 patients are susceptible to secondary bacterial infections, especially those on invasive ventilation. Therefore, we suggest tetracyclines' repurposing as a potential treatment for COVID-19 neuropsychiatric manifestations. These drugs can represent a valuable multi-modal treatment for COVID-19-associated neuroinflammatory alterations based on their broad antimicrobial profile and neuroinflammation control.

An overview of sarecycline for the treatment of moderate-to-severe acne vulgaris.

INTRODUCTION: Sarecycline is a novel, tetracycline-class antibiotic specifically designed to treat inflammatory acne. It offers a narrow spectrum of activity (mainly against Cutinebacterium acnes), and it shows less in vitro activity than other tetracyclines against enteric Gram-negative bacteria, offering advantages over older tetracyclines by decreasing the disruption of the gastrointestinal microbiome and the likelihood of developing bacterial resistance. AREAS COVERED: The drug's pharmacology, safety profile, and clinical efficacy are discussed. Results of phase I, II and III clinical trials have shown that 1.5 mg/kg/day sarecycline is safe, well tolerated and more effective than placebo in treating inflammatory acne in patients 9 years old and older. Furthermore, sarecycline's narrow spectrum of activity leads to a lower incidence of undesirable off-target antibacterial effects and consequently less adverse events such as diarrhea, fungal overgrowth and vaginal candidiasis. EXPERT OPINION: Sarecycline could become the first-line antibiotic therapy used in acne in the near future as it is an effective option for treating inflammatory acne lesions. Due to its narrow spectrum of activity, it could have a more adequate safety profile than older tetracyclines; however, head-to-head trials comparing the efficacy and safety profile of sarecycline with other tetracyclines are still needed to prove sarecycline's superiority.

Theoretical and Experimental Studies of the Controlled Release of Tetracycline Incorporated into Bioactive Glasses.

Several authors have studied the release profile of drugs incorporated in different devices. However, to the best of our knowledge, although many studies have been done on the release of tetracycline, in these release devices, no study has investigated if the released compound is actually the tetracycline, or, instead, a degraded product. This approach is exploited here. In this work, we analyse the influence of two drying methods on the tetracycline delivery behaviour of synthesised glasses using the sol-gel process. We compare the drying methods results using both theoretical models and practical essays, and analyse the chemical characteristic of the released product in order to verify if it remains tetracycline. Samples were freeze-dried or dried in an oven at 37°C and characterised by several methods such as Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TG), differential thermogravimetric analysis (DTG), differential thermal analyses (DTA) and gas adsorption analysis (BET). The released concentration of tetracycline hydrochloride was studied as a function of time, and it was measured by ultraviolet spectrophotometry in the tetracycline wavelength. The drug delivery profiles were reasonably consistent with a diffusion model analysis. In addition, we observed higher release rates for the freeze-dried compared to those dried in an oven at 37°C. This higher release can be attributed to larger pore size for the freeze-dried sample systems with tetracycline, which promoted more water penetration, improving the drug diffusion. The analysis of the solution obtained in the release tests using high-performance liquid chromatography- mass spectrometry (HPLC-MS) confirmed that tetracycline was being released.

Neutrophil elastase ameliorates matrix metalloproteinase-9 to promote lipopolysaccharide-induced acute lung injury in mice 1.

PURPOSE: To investigate the regulatory roles of neutrophil elastase (NE) and matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: To construct LPS-induced ALI mouse models, wild-type C57BL/6 mice were administered 5.0 mg/kg of LPS through endotracheal, and/or 1.0 mg/kg of ONO-5046, and/or 20.0 mg/kg of chemically modified tetracycline-3 (CMT-3) by gavage. The levels of MMP-9, tissue inhibitor of metalloprotease-1, interleukin (IL)-6 were detected by real time RT-PCR at 6 h, 24 h and 48 h, and tumor necrosis factor (TNF), lung wet-dry weight ratio, white blood cell (WBC) count and polymorphonuclear (PMN) count in bronchoalveolar lavage fluid (BALF) were tested at 48 h after administration. The 5-day survival analysis of the ALI mice was also performed. RESULTS: Both ONO-5046 and CMT-3, regardless of being used individually or combined, significantly reduced the levels of MMP-9, IL-6, and TNF in lung tissue as well as in BALF, and the WBC and PMN count in BALF. Combined treatment with ONO-5046 and CMT-3 remarkably improved the survival rate of ALI mice. CONCLUSION: Neutrophil elastase synergizes with matrix metalloproteinase-9 to promote and regulate the release of inflammatory mediators and the infiltration of inflammatory cells, consequently affecting the survival of lipopolysaccharide-induced acute lung injury mice.

Neutrophil elastase ameliorates matrix metalloproteinase-9 to promote lipopolysaccharide-induced acute lung injury in mice 1

ABSTRACT PURPOSE: To investigate the regulatory roles of neutrophil elastase (NE) and matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: To construct LPS-induced ALI mouse models, wild-type C57BL/6 mice were administered 5.0 mg/kg of LPS through endotracheal, and/or 1.0 mg/kg of ONO-5046, and/or 20.0 mg/kg of chemically modified tetracycline-3 (CMT-3) by gavage. The levels of MMP-9, tissue inhibitor of metalloprotease-1, interleukin (IL)-6 were detected by real time RT-PCR at 6 h, 24 h and 48 h, and tumor necrosis factor (TNF), lung wet-dry weight ratio, white blood cell (WBC) count and polymorphonuclear (PMN) count in bronchoalveolar lavage fluid (BALF) were tested at 48 h after administration. The 5-day survival analysis of the ALI mice was also performed. RESULTS: Both ONO-5046 and CMT-3, regardless of being used individually or combined, significantly reduced the levels of MMP-9, IL-6, and TNF in lung tissue as well as in BALF, and the WBC and PMN count in BALF. Combined treatment with ONO-5046 and CMT-3 remarkably improved the survival rate of ALI mice. CONCLUSION: Neutrophil elastase synergizes with matrix metalloproteinase-9 to promote and regulate the release of inflammatory mediators and the infiltration of inflammatory cells, consequently affecting the survival of lipopolysaccharide-induced acute lung injury mice.

Protección frente a la tinción dentaria en dientes tratados con tetraciclinas al aplicar un antioxidante (ácido ascórbico) / Protection from the tooth stain on teeth treated with tetracycline applying an antioxidant (ascorbic acid)

En la presente investigación pretendemos optimizar los resultados, evitando la coloración coronal, en procedimientos odontológicos donde sea imprescindible el uso de tetraciclinas así como evaluar la disminución de las coloraciones coronales, al aplicar un antioxidante (Acido Ascórbico) en dientes tratados con tetraciclinas (Minociclina y Doxiciclina). Estudio experimental de investigación básica, de tipo ensayo clínico. En los dientes tratados con minociclina y doxiciclina observamos cambios en la coloración dentaria apreciables tanto en corona como en la raíz, mientras que en los grupos dentarios donde se añadió el antioxidante (ácido ascórbico) a la tetraciclina no se obtuvo esa tinción. La adición de ácido ascórbico a minociclina y doxiciclina provoca que la tinción dentaria no se produzca o que se vea significativamente reducid a.

In this research we want to optimize the results, avoiding the coronal coloring, in dental procedures in where the use of tetracyclines is essential as well as evaluating the reduction of coronal discoloration, by applying an antioxidant (ascorbic acid) in the teeth treated with tetracyclines (minocycline and doxycycline). Experimental study of basic research, clinical trial type. Results: In the teeth treated with minocycline and doxycycline we observed changes in the coloration of the teeth both in crown and in the root, while in the tooth groups in which the antioxidant was added to tetracycline we observed that no staining was obtained. The addition of Ascorbic acid to minoclynine and doxyclycline causes that dental stain will not occur or be significant reduced.

MLST genotypes and antibiotic resistance of Campylobacter spp. isolated from poultry in Grenada.

This study determined whether multilocus sequence types (MLST) of Campylobacter from poultry in 2 farms in Grenada, West Indies, differed by farm, antimicrobial resistance and farm antibiotic use. Farm A used fluoroquinolones in the water and Farm B used tetracyclines. The E-test was used to determine resistance of isolates to seven antibiotics. PCR of the IpxA gene confirmed species and MLST was used to characterize 38 isolates. All isolates were either C. jejuni or C. coli. Farm antibiotic use directly correlated with antimicrobial resistance of Campylobacter isolates. Almost 80% of the isolates from Farm A were fluoroquinolone resistant and 17.9% of the isolates from Farm B were fluoroquinolone resistant. All Campylobacter isolates from Farm A were tetracycline sensitive, whereas 35.7% of isolates from Farm B were tetracycline resistant. Six previously recognized sequence types (STs) and 2 novel STs were identified. Previously recognized STs were those overwhelmingly reported from poultry and humans globally. Isolates with the same ST did not always have the same antibiotic resistance profile. There was little ST overlap between the farms suggesting that within-farm transmission of Campylobacter genotypes may dominate. MLST typing was useful for tracking Campylobacter spp. among poultry units and can help elucidate Campylobacter host-species population structure and its relevance to human health.

Terapéutica de pénfigo-no esteroidea / Non-steroid therapy in pemphigus

Se hace una revisión de los recursos terapéuticos no esteroideos, empleados en el tratamiento de las diferentes formas clínicas de pénfigo. Se enumeran los factores que condicionan la elección de dicha terapéutica; forma clínica, edad, embarazo, concomitancia con otras enfermedades, interacción con otros fármacos y efectos adversos. El esteroide continúa siendo la droga de primera elección, debiendo estar asociado con otras medicaciones adyuvantes, habitualmente desde su inicio, a fin de promover un descenso más rápido del mismo, con menor incidencia de complicaciones. En los pénfigos graves se preferirá su asociacián con inmunosupresores, en primer lugar con la azatioprina o bien con ciclofosfamida. La dapsona, como las tetraciclinas, será alternativa para algunas formas más leves de pénfigo, mientras que los pulsos de ciclofosfamida, así como la plasmaféresis, deberán reservarse para aquellos casos graves que no hayan respondido a las terapéuticas convencionales (AU)

Osteoma cutis miliar multiple / Multiple miliary osteoma cutis

El osteoma cutis miliar múltiple (OCMM) está caracterizado por múltiples nódulos firmes y pequeños formados por crecimientos óseos nuevos que aparecen en la piel. Los autores describen una paciente de 60 años con lesiones de aparición progresiva de tres años de evolución, asintomáticas, localizadas en ambas mejillas, con antecedentes de acné en la adolescencia, los exámenes paraclínicos (entre ellos calcio, fósforo y paratohormona) no evidenciaron alteraciones. Los OCMM no están relacionados con hipercalcemia o calcinosis y existe mucha controversia sobre su origen así como la influencia de lesiones o inflamación previa como factores etiológicos. Se analizan las hipótesis así como la clasificación y exámenes complementarios de dinámica ósea y tratamiento

Evaluación prospectiva del tratamiento de acne complicado con tetraciclina e ibuprofen / Prospective evaluation of complicated acne treatment with tetracycline and Ibuprofen

Se hizo un estudio prospectivo randomizado en 75 pacientes divididos en tres grupos. Uno tratado con tetraciclina, un segundo grupo con Ibuprofen, y otro grupo con la combinación Ibuprofen más Tetraciclina. Todos por ocho semanas de tratamiento. El esquema Ibuprofen más Tetraciclina fue efectivo y bién tolerado