Hypothesizing the potential implications of exposing known carcinogens on normal stem cells

Publication date: Available online 5 March 2018
Source:Oral Oncology
Author(s): A. Thirumal Raj, Supriya Kheur




http://ift.tt/2Ft6uEd

An enlarging nodule on the shin

http://ift.tt/2oKzEp8

Otoemisiones en los niños tratados con gentamicina de un hospital comarcal

Publication date: Available online 5 March 2018
Source:Acta Otorrinolaringológica Española
Author(s): Jose Miguel Sequi Canet, Carlos Miguel Angelats Romero, Jose Miguel Sequi Sabater, Ana Miralles Torres, Miguel Boronat Garcia, Marta Gomez Delgado
IntroducciónLas recomendaciones de la Comisión Nacional para la Detección Precoz de la Hipoacusia (CODEPEH) aconsejan re-valorar la audición de aquellos niños que hayan sufrido algún evento potencialmente dañino para la audición como es la utilización de antibióticos ototóxicos como la gentamicina. Las otoemisiones evocadas son un buen método de evaluación de la integridad de la función coclear.Material y métodoSe presenta un estudio prospectivo que incluye a 92 niños, sin otros factores de riesgo auditivo, en los que se pautó tratamiento con gentamicina intravenosa por riesgo séptico/sepsis o infección urinaria y en los que se realizaron otoemisiones seriadas: al ingreso, al finalizar el tratamiento y al mes del alta (si estaban alteradas).ResultadosNingún sujeto presentó otoemisiones alteradas al final del seguimiento.ConclusiónLa gentamicina parece un antibiótico seguro en tratamientos con una duración <10días y a las dosis descritas. Las otoemisiones son un método barato, rápido, incruento y fiable para comprobar la posible ototoxicidad por gentamicina. Su realización podría ahorrar la determinación de niveles del fármaco.IntroductionThe National Commission for the Early Detection of Hearing Loss (CODEPEH) recommends the re-evaluation of hearing in children who have suffered any potentially harmful event, such as the prescription of ototoxic antibiotics such as gentamicin. The evoked otoacoustic emissions (EOAE) are a good method for assessing the integrity of cochlear functionality.Material and methodA prospective study is presented, including 92 children who were treated with intravenous gentamicin for septic risk/sepsis or urinary tract infection. The children underwent serial EOAE: on admission, at the end of treatment and one month later (if altered on discharge).ResultsIn the end, none of the subjects were affected by the treatment.ConclusionGentamicin appears to be a safe antibiotic in treatments lasting <10days and at the doses described. EOAE are an inexpensive, fast, non-invasive and reliable method to check for gentamicin ototoxicity. This could save in the determination of drug levels.



http://ift.tt/2oSEakB

Model-based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection: A Pilot Study [PublishAheadOfPrint]

Background: Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. Target area under the concentration versus time curve (AUC_0–24) of 40-50 μg·h/mL is recommended. The standard dose resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization in this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach.

Methods: The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC_0-24 to ensure the efficacy.

Results: A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC_0-24 after giving the standard dose. For all the subtherapeutic (below 80% target AUC) patients (n=5), model-based dosage adjustment was performed using Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased 28.6% - 60.0% in these five patients and all adapted AUC_0–24 achieved the target (range: 48.6-66.1 μg·h/mL).

Conclusion: The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. Population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinical feasible method to adapt ganciclovir dose in neonatal clinical practice.

http://ift.tt/2D273Qr

The effect of antimicrobial agents on inflammatory cytokines in acute leptospirosis [PublishAheadOfPrint]

The aim of this study was to assess the inflammatory cytokine response and possible association with antimicrobial treatment with penicillin, ceftriaxone and doxycycline in acute leptospirosis. In the early acute stage, IL-10 was higher in mild cases compared to severe cases (p=0.01). IL-6 and IL-8 levels were low in patients who received >5 antimicrobial doses (p<0.01). IL-8 was negatively correlated with number of ceftriaxone doses administered (r=-0.315; p=0.031). Further studies are needed to evaluate the possible down-regulation of pro-inflammatory cytokines by ceftriaxone in leptospirosis.

http://ift.tt/2FWcXW8

Topical treatment for cutaneous leishmaniasis - dermato-pharmacokinetic led optimisation of benzoxaboroles [PublishAheadOfPrint]

Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania – affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focussed primarily on drug permeation and formulation optimisation as the means to increase treatment efficacy.

Our approach aims to identify compounds with anti-leishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (EC₅₀< 5 μM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 μM< EC₅₀ <30 μM) against two more species. Benzoxaborole compounds were further prioritised based upon the in vitro evaluation of progression criteria related to skin permeation such as the partition coefficient and solubility. An MDCK-MDR1 assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but have superior stability than para-hydroxybenzoate compounds that are known skin esterase substrates. Permeation evaluation through reconstructed human epidermis showed LSH002 to be most permeable followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001 followed by LSH003 and LSH002 with a significantly higher amount of LSH001 retained in skin compared to other compounds.

Finally, the efficacy of the leads (LSH001, LSH002 and LSH003) was tested in vivo against Leishmania major. LSH001 suppressed lesion growth upon topical application and LSH003 reduced the lesion size following oral administration.

http://ift.tt/2D3OI5b

Relebactam (MK-7655) in combination with imipenem: Exploring the pharmacokinetic/pharmacodynamic relationship with a hollow fiber infection model [PublishAheadOfPrint]

Resistance to antibiotics among bacterial pathogens is rapidly spreading and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (MK-7655; REL) in a hollow fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow fiber infection model to confirm the efficacy of human exposures associated with the Phase 2 doses (imipenem 500 mg + REL 125 or 250 mg administered intravenously every 6 hours as a 30-minute infusion) against imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae. Dose fractionation experiments confirmed that the pharmacokinetic parameter best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the minimum inhibitory concentration (MIC) of imipenem as dynamic: it changes with time and this change is directly related to REL levels. For the strains tested, the percentage of time above dynamic MIC for imipenem was maintained at the carbapenem target of 30-40%, required for maximum efficacy, for imipenem 500 mg plus REL 250 mg.

http://ift.tt/2FXC8aP