Thesis (Ph. D.)--State University of New York at Stony Brook, 1996. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--State University of New York at Stony Brook, 1996. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Diss. (sammanfattning) Göteborg : Univ. , 2007. / Härtill 5 uppsatser.

Minocycline (MC) and Doxycycline (DC) are used worldwide as locally applied adjuncts in the treatment of periodontal diseases. As a group the tetracyclines are well known for their advantageous properties. There is however possible cytotoxicity towards cells in the area of application. This study determined the minimum cytocidal concentration of MC and DC on the growth and proliferation of Human Periodontal Ligament Fibroblasts (HPLF) in vitro. This was facilitated by growing cells (PDL1 and PDL2) in the presence of MC and DC in media in 96 tissue wells starting at a concentration of 1400 µg.ml-1 (100%). Serial dilutions of the MC and DC at 10% increments were investigated in order to detect significant HPLF cell growth inhibition. The significant LD50 was further determined at one percent increments in order to arrive at a specific percentage value. The results were read as LD50 values from growth concentration curves. The LD50 of MC on PDL1 and PDL2 after one hour exposure was 686 µg.ml-1 and 896 µg.ml-1 respectively while for DC it was 252 µg.ml-1 and 546 µg.ml-1. The LD50 of MC on PDL1 and PDL2 after 24 hour exposure was 196 µg.ml-1 and 266 µg.ml-1 respectively while for DC it was 252 µg.ml-1 for both. The LD50 of MC on PDL1 and PDL2 after 48 hour exposure was 252 µg.ml-1 and 182 µg.ml-1 respectively while for DC it was 154 µg.ml-1 and 168 µg.ml-1. Based upon the LD50 values this study found that DC is more cytotoxic than MC and linked to this, the two cell lines reacted slightly differently. The concentrations MC and DC tested in this study did however not influence growth of HPLF significantly. / Dissertation (MChD)--University of Pretoria, 2010. / Oral Pathology and Oral Biology / unrestricted

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A depressÃo à um dos mais prevalentes transtornos psiquiÃtricos. Os principais sintomas clÃnicos da depressÃo sÃo humor deprimido, anorexia, anedonia, reduÃÃo da atividade locomotora. Hà evidÃncias acumuladas de que a depressÃo pode se desenvolver em resposta à ativaÃÃo do sistema imune inato, sendo caracterizada por uma resposta inflamatÃria com aumento da produÃÃo de interleucina IL-1β, IL-6, TNF-α e outras. Com base nas propriedades anti-inflamatÃrias e antioxidantes da doxiciclina e supondo que esta droga apresenta menos efeitos colaterais e um melhor perfil farmacocinÃtico, em comparaÃÃo com a minociclina, a hipÃtese de que esta droga pode apresentar efeitos antidepressivos, utilizando o modelo de depressÃo induzido por lipopolissacarÃdeo (LPS) foi estudada. Para determinar as alteraÃÃes de comportamento, camundongos Swiss machos foram submetidos aos testes de campo aberto e nado forÃado. Para avaliar a capacidade da doxiciclina em prevenir ou reverter o comportamento tipo-depressivo induzido pela administraÃÃo sistÃmica de LPS, esta foi administrada nas doses de 25 ou 50 mg/kg, i.p. 30 min antes de LPS (prÃ-LPS) ou 1,5 e 23,5 horas apÃs a LPS (pÃs-LPS). A imipramina foi utilizada como antidepressivo padrÃo nas mesmas condiÃÃes de tempo. Em ambas as situaÃÃes, prevenÃÃo (prÃ-LPS) e tratamento (pÃs-LPS), o comportamento dos animais foi avaliado 24 horas apÃs a administraÃÃo de LPS, um perÃodo conhecido pela ocorrÃncia de um comportamento tipo-depressivo. Os nÃveis de citocinas (IL-1β e TNF-α) e nitrito foram avaliados no sangue (plasma) e as Ãreas cerebrais: cÃrtex prÃ-frontal (PFC), hipocampo (HC) e corpo estriado (ST). A administraÃÃo de LPS, 0,5 mg/kg aumentou significativamente o tempo de imobilidade em comparaÃÃo com os animais controle, enquanto que a doxiciclina, nas doses de 25 e 50 mg/kg e imipramina (10 mg/kg) foram capazes de prevenir e reverter a imobilidade induzida pelo LPS. A doxiciclina e imipramina, quando administrados prà e pÃs-LPS reduziram significativamente o tempo de imobilidade, mostrando um efeito antidepressivo. Em relaÃÃo a citocina IL-1β, seus nÃveis foram diminuÃdos, enquanto os nÃveis de TNF-α nÃo foram alterados significativamente. A doxiciclina e imipramina, preveniram e reverteram a diminuiÃÃo dos nÃveis de nitrito induzido por LPS. Com base nos resultados do presente estudo, avaliando o uso da doxiciclina, sugere-se que este antimicrobiano possa atuar como um antidepressivo. / Current evidences support inflammation, oxidative and nitrogen stress, as well as brain-derived neu-rotrophic factor (BDNF) signaling mechanisms as important in depression pathophysiology. Tetracycline antibiotics have anti-inflammatory and antioxidant properties. Preliminary evidence indicates that minocycline has antidepressant properties. Doxycycline (DOXY) has favorable pharmacokinetic and safety profiles when compared to other tetracycline congeners. The antidepressant activity of DOXY has not been adequately investigated. This study evaluated the effects of DOXY (25 and 50 mg/kg, i.p.) on LPS-induced (0.5 mg/kg, i.p.) depressive-like behavior. Doxycycline was administered 30 min before LPS (pre-LPS) or 1.5 and 23.5 h following LPS (post-LPS) administration in mice. LPS-treated animals pre-sented an increase in immobility time in the forced swimming test (FST) when compared to controls 24 h after endotoxin administration. Similarly to imipramine (IMI-10 mg/kg, i.p.), DOXY at both doses pre-vented and reversed LPS-induced alterations in the FST. IL-1b content was increased 24 h after LPS administration in striatum, hippocampus and prefrontal cortex. IMI and DOXY prevented and reversed LPS-induced increase in IL-1b. IMI and DOXY also prevented and reversed LPS-induced alterations in nitrite content and oxidative stress parameters (lipid peroxidation and reduced glutathione levels). Both DOXY and IMI prevented LPS-induced decrease in hippocampal BDNF levels. Taken together, our results demonstrate that DOXY is comparable to IMI in effectively ameliorate LPS-induced depressive-like behavior, providing a rationale for testing DOXYâs antidepressant efficacy in humans.

Thèse de doctorat : Médecine. Virologie : Université de Nantes : 2004. / Bibliogr. f. 144-172.

Thèse (M.Sc.)--Université Laval, 2009. / Bibliogr. Publié aussi en version électronique dans la Collection Mémoires et thèses électroniques.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A Pilocarpina à um agonista colinÃrgico caracterÃstico por induzir convulsÃes que evoluem para status epilÃpticus, similar à epilepsia do lobo temporal humana. Neste presente trabalho, nÃs avaliamos a possÃvel aÃÃo neuroprotetora da doxiciclina, uma tetraciclina de segunda geraÃÃo, nas convulsÃes induzidas pela pilocarpina em ratos Wistar machos, que receberam pilocarpina (300mg/kg i.p) presenÃa ou na ausÃncia de doxiciclina (25 à 100 mg/kg) administrada intraperitonealmente uma vez ao dia durante sete dias. ApÃs a injeÃÃo de pilocarpina, foram observados os sinais colinÃrgicos perifÃricos, as latÃncias de 1 convulsÃo e de morte. Foram determinadas as concentraÃÃes de aminoÃcidos no cÃrtex temporal atravÃs de cromatografia lÃquida de alta eficiÃncia HPLC, e a atividade do sistema antioxidante, catalase e as dosagens dos nÃveis de TBARS e nitrito. Os resultados mostraram que a doxiciclina nÃo alterou os sinais colinÃrgicos perifÃricos, contudo aumentou a latÃncia decorrida para a primeira convulsÃo (1.6 a 5 vezes), quando comparada ao grupo (P300). Resultados semelhantes foram demonstrados com a latÃncia de morte, que foi aumentada de 1.9 a 9.9 vezes. Observou - se que o prÃ-tratamento com doxiciclina 50 mg/kg foi capaz de reduzir em 25% os nÃveis de MDA, 64% os nÃveis de nitrito e 67.7% a atividade da catalase no cÃrtex temporal desses animais, demonstrando com clareza seu potencial antioxidante. Interessantemente, a doxiciclina diminuiu as concentraÃÃes de glutamato de 28 a 33%, e aumentou GABA em 112 e 91%, nas dose de 50 e 100mg/kg respectivamente nos animais administrados com P300, Na maior dose, a droga alterou os nÃveis de aspartato e taurina, diminuindo em 61% aspartato enquanto elevou os nÃveis de taurina em cerca de 34%. Surpreendentemente, somente a menor dose alterou os nÃveis de glicina, aumentendo a concentraÃÃo deste aminoÃcido em 132%. Em conclusÃo, mostramos que o inÃcio e a intensidade das convulsÃes induzidas pela pilocarpina foram significativamente reduzidos pela doxiciclina. Portanto, pelo menos em parte, este mecanismo de aÃÃo parece estar relacionado a uma diminuiÃÃo nos nÃveis de aminoÃcidos excitatÃrios e a um aumento nas concentraÃÃes de aminoÃcidos inibitÃrios no cÃrtex temporal desses animais. / Pilocarpine is known to induce convulsions leading to status epilepticus, similar to the temporal lobe epilepsy in humans. In the present work, we evaluated the possible protection affored by doxycyvline, a 2nd generation tetracycline, agaist pilocarpine- induced convulsions in male Wistar rats (P300mg/kg, i.p) in the absence and in the presence of doxicycline (25 to 100 mg/kg i.p.) daily for 7 days.After the pilocarpine injection, all groups were observed for cholinergic signs, latency to the first convulsion and latency to death. Besides, amino acid concentrations in temporal cÃrtices were determined by RP-HPLC, as well catalase activity and levels of TBARS and Nitrite. Results showed that doxycycline did not alter cholinergic signs but increased the latency time to the first convulsion (1.6 to 5 times increase), as compared to P300, and the highest effect was observed with the dose of 25 mg/kg. Similar results were demonstrated to death latency that increased from 1.9 to 9.9 times with doxyciclyne at the doses of 25, 50 and 100 mg/kg. In fact we showed that the pre-treatment with doxycycline decreased in 25% MDA levels, 64% nitrite levels and 67.7% catalase activity. Interestingly, doxycycline decreased glutamate concentrations in 28 and 33% and increased GABA in 112 and 91% at the doses of 50 and 100mg/kg respectively. At the higher dose the drug altered aspartate and taurine concentrations, decreased aspartate levels in 61%, while increasing taurine levels in 34%. Surprisingly, only the lower dose altered glycine levels, increasing its concentration by 132%. In conclusion, we showed that the onset and intensity of pilocarpine-induced seizures were significantly reduced by doxycycline. Furthermore, at least in part, its mechanism of action seems to be mediated by the decrease and increase of excitatory and inhibitory aminoacids, respectively. In addiction the doxycycline capacity to reduce the oxidative stress associated with the pilocarpine-induced may also play a role

Thèse de doctorat : Physiologie et physiopathologie de l'appareil respiratoire : Paris 12 : 2005. / Version électronique uniquement consultable au sein de l'Université Paris 12 (Intranet). Titre provenant de l'écran-titre. Bibliogr.

Tetracycline molecules including doxycycline (DOX), consist of a group of broad-spectrum antibiotics. In addition, tetracyclines inhibit matrix metalloproteinase (MMPs) that contribute to tissue remodeling, inflammation, angiogenesis and are over-expressed in certain pathologies - such as Alzheimer’s disease, metastasis and diabetic foot ulcers (DFUs). Tetracyclines are hypothesized to inhibit MMPs through the chelation and sequestration of catalytic divalent ions such zinc and calcium. This inhibitory duality may be beneficial in pathologies that are characterized by MMP over-expression and prone to infection, such as DFUs. Compared to oral administration, topical DOX is an attractive route of administration for chronic wound healing as it may minimize the risks: associated antibiotic resistance; is being targeted directly to the wound bed. However, DOX is notoriously unstable in aqueous solution and common topical formulations. Liquid chromatography and mass spectrometry (LCMS) were employed to monitor stability using an in vitro MMP assay and an applicable E. coli anti-bacterial assay was assessed to quantify drug activity. 2 % (w/w) topical DOX demonstrated an acceptable stability 30 day when stored at 4 ºC. DOX inhibited MMP9 activity with an IC50 value of 48.27 μM. With respect to anti-bacterial activity, using cultured BL21 E.Coli and quantification of drug activity as an expression of colony forming units (CFUs) successfully reproduced the antimicrobial IC50 of doxycycline as 4.3 µM. Transdermal DOX has the potential to improve standard of care for DFUs, quality of life for the patient and reduce costs to the healthcare system. / Thesis / Master of Science (MSc) / Tetracyclines comprise of a group of broad-spectrum antibiotics; whose primary mechanism of action is inhibition of protein synthesis through binding of the bacterial ribosome. In addition, tetracyclines inhibit matrix metalloprotease (MMPs), zinc-dependent proteases that contribute to tissue remodeling, angiogenesis and are over-expressed in certain pathophysiologies such as diabetic foot ulcers (DFUs). The antibacterial mechanism of DOX on MMPs is reported and understood, however the inhibition is hypothesized to involve cation chelation. Thus, investigating this interaction is warranted to assist in developing a therapeutic for DFUs. A more logical product would involve direct topical application, such as a stable transdermal formulation of DOX.