Effectiveness and clinical implications of the use of topical antibiotics in regenerative endodontic procedures: a review.

Regenerative endodontic procedures (REPs) are biologically based procedures planned to replace damaged tissues, including dentinee and root structures, as well as cells of the pulp-dentine complex. Effective sterilization of the root canal is essential in REPs, and antibiotics have been widely used to disinfect root canals. The aim of this paper was to review the scientific literature on (i) Effectiveness of antibiotics used in REPs against bacteria implicated in endodontic disease; (ii) Scientific evidence supporting the use of topical antibiotics in REPs; (iii) Clinical implications of the use of antibiotics in REPs and the possible side effects; (iv) Effect of antibiotics on dental pulp stem cells; and (v) Ongoing research on the use of antibiotics in REPs. Antibiotics used in REPs are effective against bacteria implicated in endodontic infections. Triple antibiotic pastes with minocycline attain complete disinfection of immature teeth with necrotic pulps, without affecting SCAP. Experimental studies carried out in dogs support the use of antibiotics in REPs. Clinical studies report high success rates of RET using antibiotics as intracanal dressings. However, tooth discolouration is an important side effect of the use of TAP. An antibiotic paste containing only metronidazole and ciprofloxacin could be a good alternative to the use of TAP. The use of antibiotic-containing scaffolds or clindamycin-modified triple antibiotic (metronidazole, ciprofloxacin and clindamycin) polymer could be a biologically safe antimicrobial drug delivery system in REPs.

Dental students' knowledge regarding the indications for antibiotics in the management of endodontic infections.

AIM: To determine the knowledge of undergraduate Spanish dental students regarding the indications of systemic antibiotics in the management of endodontic infections. METHODOLOGY: The final year dental students from four Spanish dental schools were requested to answer a one-page questionnaire on the indications for systemic antibiotics in the treatment of endodontic infections. One hundred and seventy-five students were asked to participate in this research. Data were analysed using descriptive statistics and chi-square test. RESULTS: One hundred and four students (93.7%) completed satisfactorily the survey and were included in the study. The average duration of antibiotic therapy was 7.0 ± 2.0 days. All respondents chose amoxicillin as the first-choice antibiotic in patients with no medical allergies, alone (47%) or associated with clavulanic acid (53%). The first drug of choice for patients with an allergy to penicillin was clindamycin 300 mg (99%). For cases of irreversible pulpitis, up to 63% of students would prescribe antibiotics. For the scenario of a necrotic pulp, symptomatic apical periodontitis and no swelling, 44% would prescribe antibiotics. Almost 40% of students would prescribe antibiotics for necrotic pulps with asymptomatic apical periodontitis and a sinus tract. CONCLUSIONS: It is necessary for the Spanish schools of dentistry to improve students' knowledge about antibiotics and their indications in endodontics. Interactive education analysing real endodontic cases using problem-based learning would help students acquire better skills in prescribing antibiotics in pulp-periapical pathosis.

Aplicación de la estrategia secuencial de la OCDE para evaluar la irritación y corrosión dérmica por un producto fitosanitario / Application of the OCDE sequential strategy for the evaluation of dermal irritation and corrosion

Con la intención de reemplazar los ensayos en animales y mejorar las propiedades predictivas, la Guía TG404 de la OCDE sobre irritación/corrosión dérmica aguda ha desarrollado una nueva estrategia secuencial que promueve el uso de métodos alternativos tales como los test en sistemas in vitro. Se ha aplicado el procedimiento de esta estrategia para evaluar la irritación y corrosión dérmica por un nuevo fertilizante con fines de registro, con el objetivo de comprobar sus ventajas en un estudio normalizado. Para evaluar la corrosión dérmica se ha utilizado el sistema in vitro validado EpiDerm™, epidermis reconstituída formada por queratinocitos humanos. Puesto que por el momento no existe un modelo in vitro validado para irritación dérmica, ésta fue evaluada en el sistema EpiDerm™ y mediante un método in vivo. En ambos ensayos in vitro se midió también la liberación de IL1α. El producto fue clasificado como no corrosivo y no irritante. Los resultados del estudio demuestran las ventajas de la estrategia secuencial propuesta por la OCDE en la evaluación de la corrosión e irritación por las siguientes razones: a) se adquiere un conocimiento previo sobre las propiedades físicoquímicas de los compuestos químicos con el fin de evitar la exposición innecesaria de los animales a sustancias corrosivas b) los métodos in vitro de corrosión dérmica pueden sustituir los animales de experimentación c) las modificaciones propuestas para el test in vivo reducen el sufrimiento de los animales y suponen un importante ahorro económico y de tiempo. No obstante, se requiere con urgencia disponer de métodos alternativos in vitro para evaluar la irritación cutánea

In order to replace the assays carried out on animals and improve the predictive properties, the Guideline TG404 of the OCDE on acute dermal corrosion/irritation has developed a new sequential strategy that promotes the use of alternative methods such as the tests in in vitro systems. The procedure of this strategy has been applied in order to evaluate the irritation and dermal corrosion produced by a new fertilizer with the objective of obtaining a patent and in order to determine the advantages of using said fertilizer in a normalized study. In order to evaluate the dermal corrosion, the validated in vitro system EpiDermTM, a reconstituted epidermis formed by human keratinocytes, has been used. Since, at this moment, no in vitro model which is validated for dermal irritation exists, this method was evaluated in the EpiDermTM system and by means of and in vivo method. In both in vivo assays, the release of IL1α was measured also. The product was classified as noncorrosive and nonirritant. The results of the study showed the advantages of the sequential strategy proposed by the OCDE in the evaluation of the corrosion and irritation due to the following reasons: a) prior knowledge is acquired regarding the physicochemical properties of the chemical compounds for the purpose of avoiding unnecessary exposure of corrosive substances to the animals; b) the in vitro methods of dermal corrosion can substitute the experimentation animals and c) the modifications proposed for the in vivo test reduce animal suffering and represent important time and economical savings. However, there is an urgent need for available alternative in vitro methods for the evaluation of cutaneous irritation

Immunotoxic effects of Ochratoxin A in Wistar rats after oral administration.

Ochratoxin A (OTA) is a mycotoxin produced by species of the genus Aspergillus and Penicillium. Human exposure has been demonstrated worldwide and its origin seems to be the intake of contaminated foods. The kidneys are the target organ of this mycotoxin. Immunotoxic and genotoxic effects of OTA were investigated in Wistar male rats (aged 12 weeks), treated by gavage with 50, 150 or 450 microg OTA/kg body weight for 28 days, in the context of a general toxicity study, which was designed following the recommendations of OECD guideline 407. At the end of the study, the mean plasma concentration of the mycotoxin was determined, several immune function assays were performed and bone marrow smears were obtained and stained in order to analyse micronuclei in polychromatic erytrocytes. Mean plasma concentration was found to be 187, 600 and 807 microg/L, respectively. At the highest dose, a decrease in body weight gain was observed. Histopathological investigations revealed tubulonephrosis and acute tubular necrosis in the kidneys of the animals treated with OTA. The frequency and severity of the lesions increased with the dose. The response of splenocytes to sheep red blood cells was decreased in a dose-dependent manner; however, nonstatistically significant differences were obtained. The natural killer cell activity was strongly affected by OTA treatment. Cytotoxic T lymphocyte activity was lower in the animals exposed to 50 microg OTA/kg b.w. but was not modified in the groups exposed to 150 and 450 microg OTA/ kg b.w. The bacteriolytic capability of macrophages was significantly reduced in groups exposed to 50 and 450 microg OTA/ kg b.w. The number of micronuclei in bone marrow polychromatic erytrocytes did not vary significantly with respect to the control at any dose, but a false negative result can not be ruled out because the exposure doses were much lower than those recommended in OECD guideline 474.

¿Es la ocratoxina a una micotoxina mutagénica? / Is the ochratoxin A a mutagenic mycotoxine?

La ocratoxina A es una micotoxina producida por especies de los géneros Aspergillus y Penicillium que a través de los alimentos puede pasar al ser humano. Su órgano diana es el riñón pero también es hepatotóxica, inmunotóxica y teratogénica. Ha sido clasificada por la Agencia Internacional de Investigación contra el Cáncer (IARC) como posible carcinógeno humano (clase 2B) pero se desconoce si el mecanismo de acción transcurre a través de fenómenos genéticos o epigenéticos. En este artículo se revisan los datos de genotoxicidad y mutagenicidad de esta micotoxina. Aunque los primeros estudios en ensayos de reversión mutagénica con bacterias resultaron negativos, pronto se comprobó que administrada a animales de experimentación, la ocratoxina A inducía la formación de aductos especialmente en tejidos de riñón y vejiga urinaria de ratón. También se ha comprobado que esta micotoxina produce roturas monocatenarias en el ADN, da lugar a alteraciones cromosómicas e intercambios entre cromátidas hermanas e induce la síntesis de ADN fuera del período S, fenómeno indicativo de procesos de reparación. Se considera que la actividad genotóxica es dependiente de activación metabólica, en particular de varias isoformas P450, si bien los metabolitos genotóxicos no han sido aislados. Los últimos estudios realizados con ocratoxina A tritiada bajo diversas condiciones experimentales indican que el principal metabolito es el derivado monohidroxilado 4(R) - hidroxi-ocratoxina A y que ni la ocratoxina A ni este metabolito forman aductos con el ADN, por lo que su actividad genotóxica estaría más relacionada con procesos de citotoxicidad y peroxidación lipídica, los cuales podrían dar lugar a moléculas reactivas con los ácidos nucleicos (AU)

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1,2,5-Oxadiazole N-oxide derivatives as potential anti-cancer agents: synthesis and biological evaluation. Part IV.

Several new 1,2,5-oxadiazole N-oxide derivatives and some deoxygenated analogues were synthesized to be tested as potential selective hypoxic cell cytotoxins. Compounds prepared were designed in order to gain insight into the mechanism of action of this kind of cytotoxin. Compounds were tested in oxia and hypoxia and they proved to be non-selective. 3-Cyano-N(2)-oxide-4-phenyl-1,2,5-oxadiazole showed the best cytotoxic activity in oxia. The cytotoxicity observed for these derivatives could be explained in terms of the electronic characteristics of the 1,2,5-oxadiazole substituents. Electrochemical and ESR studies were performed on the more cytotoxic derivative.

Synthesis and biological evaluation of 1,2,5-oxadiazole N-oxide derivatives as potential hypoxic cytotoxins and DNA-binders.

Several new 1,2,5-oxadiazole N-oxide derivatives were synthesized to be tested both as potential selective hypoxic cell cytotoxins and as DNA-binding agents. The compounds prepared included bis(1,2,5-oxadiazole N-oxide) derivatives and oxadiazole rings linked to naphthyl residues. The compounds were tested for their cytotoxicity in oxia and hypoxia and they proved to be non-selective and less active than the parent compounds 3-formyl-4-phenyl-1,2,5-oxadiazole N2-oxide (3) and 3-chloromethyl-4-phenyl-1,2,5-oxadiazole N2-oxide (4). The DNA-affinity assays showed that the compounds tested have poor affinity for this biomolecule.

Efectos tóxicos de la Ocratoxina A / Toxic effects of Ochratoxin A

La ocratoxina A (OTA) es una micotoxina producida por hongos micomicetos de los géneros Aspergillus y Penicillium que se encuentra ampliamente distribuída como contaminante natural de cereales, legumbres y otros alimentos y que en estudios experimentales ha demostrado una gran diversidad de efectos tóxicos. Debido a sus propiedades fisicoquímicas, la OTA se absorbe fácilmente del tracto gastrointestinal, siendo su biodisponibilidad superior ai 50 por ciento en todas ias especies de mamíferos ensayadas. Presenta una alta afinidad por las proteínas plasmáticas, lo que determina una larga persistencia en el organismo. Los principales metabolitos son el producto de hidrólisis del enlace amida (OTalfa), los derivados hidroxilados 4-OH-OTAy 10-OH-OTAy los productos de conjugación, entre otros. Se elimina por vía renal y hepatobiliar, así como también a través de la secreción lactea. La DL50 oscila entre 0,2 y 58,3 mg/kg pc; perros, cerdos y pollos son especies más sensibles que rata y ratón. La ingestión crónica de OTA da lugar a la aparición de un efecto tóxico renal en todas las especies de mamíferos monogástricos testados. Se ha relacionado con la nefropatía porcina, la nefropatía aviar espontánea, y en el hombre con la nefropatía endémica de los Balcanes. Diversos estudios han puesto de manifiesto efectos tóxicos de la OTA sobre; el sistema inmune y sobre el sistema nervioso. Tiene también un efecto hemorrágico semejante al que se produce por carencia de vitamina K y altera el metabolismo de los hidratos de carbono, provocando una acumulación de glucógeno en el hígado. El principal mecanismo de acción es la inhibición de la síntesis protéica a nivel post-transcripcional por inhibición competitiva de la Phe-tRNA sintetasa; también se ha descrito un efecto inductor de peroxidación lipídica. La OTA ha resultado teratogénica en ratón, rata, hamster y gallina, con el sistema nervioso central como principal diana. La OTA incrementa la formación de aductos, induce micronúcleos, intercambios entre cromátidas hermanas y mutación génica en Salmonella typhimurium tras activación metabólica. Está clasificada por la IARC como posiblemente carcinogénica para el hombre (grupo 2B) debido a que induce adenomas renales y carcinomas en ratas y ratones, si bien los datos en el hombre no son concluyentes (AU)

Synthesis and biological evaluation of 1,2,5-oxadiazole N-oxide derivatives as hypoxia-selective cytotoxins.

Synthesis and biological evaluation of new 1,2,5-oxadiazole N-oxide derivatives with potential cytotoxic effects are described. From the series of compounds tested, compounds 2 and 6 proved to be very active, although non-selective.