Abstract Chronic Chlamydia pneumoniae infections have been associated with cardiovascular diseases (CVD), but the treatment is difficult. Some drugs used for CVD have been found to have an inhibitory effect on the C. trachomatis infection, which is not considered to be associated with CVD. The purpose of this study was to investigate the effects of heparan sulfate-like glycosaminoglycans, COX inhibitors and rapamycin on the C. pneumoniae infection with cell culture methods. Almost any conceivable factors may affect the results of cell cultures. This study showed the complex interaction between temperature, time and medium during the pre-treatment before inoculation. The influences of these factors on the results overlapped and interlaced. The simple washing procedure could enhance the infectivity of C. pneumoniae although it is generally considered to cause the loss of chlamydial EBs and sequentially decrease the chlamydial infectivity. Although the detailed mechanisms were not studied, the results of this study showed that selective COX inhibitors and rapamycin can inhibit the infectivity of C. pneumoniae by inhibiting the growth and maturation, whereas heparan sulfate-like glycosaminoglycans perhaps inhibit the attachment of C. pneumoniae EBs onto the host cells. Recovery and repassage results showed that the growth can be only delayed by selective COX inhibitors, and it can recover to normal level once the drugs were removed. However, rapamycin inhibited the maturation of chlamydial EBs and therefore the infectivity fell down further even when the rapamycin was removed. This study also presented the variations of pathogenicity between different C. pneumoniae strains in vitro. This study is based on in vitro experiments with an acute infection model. Thus, any definite conclusions on the possible antichlamydial effects of the drugs tested in the treatment of cardiovascular diseases which are associated with chronic C. pneumoniae infections cannot be drawn on the basis of this study.

No description available.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / IntroduÃÃo: A via da hemeoxigenase-1 (HO-1) possui aÃÃes antioxidantes. Por outro lado, a ciclo-oxigenase 2 (COX-2) està envolvida na patogÃnese de muitas doenÃas inflamatÃrias e sua inibiÃÃo seletiva reduz eventos inflamatÃrios sem efeitos gÃstricos. Entretanto, ensaios clÃnicos demonstraram que os inibidores seletivos de COX-2 estÃo associados com efeitos cardiovasculares. Objetivo: Avaliar a interaÃÃo entre as vias da HO-1/BVD/CO e da COX-2 no controle da nocicepÃÃo e da inflamaÃÃo. MÃtodos: Protocolo 1: No modelo de contorÃÃo abdominal induzido por Ãcido acÃtico, camundongos foram prÃ-tratados com etoricoxibe (inibidor seletivo da COX-2; 0,1, 1 ou 10mg/Kg; i.p) ou com moduladores da via HO-1/BVD/CO, a saber: Hemina (substrato da via HO-1/BVD/CO; 0,3, 1, ou 3mg/Kg; s.c), DMDC (doador de CO; 0,00025, 0,025 ou 2,5ÂMol/Kg; s.c) ou ZnPP-IX (inibidor especÃfico da HO-1; 1, 3 ou 9mg/Kg; s.c). Os animais prÃ-tratados com etoricoxibe ou com os moduladores da via HO-1/BVD/CO receberam, apÃs 30 e 60 min, respectivamente, a injeÃÃo (i.p) de Ãcido acÃtico, seguido da quantificaÃÃo do nÃmero de contorÃÃes abdominais. Realizou-se ainda no mesmo modelo a coadministraÃÃo de doses inefetivas de etoricoxibe com hemina ou DMDC e de uma dose efetiva de etoricoxibe com ZnPP-IX. ApÃs 4 h da injeÃÃo de Ãcido acÃtico, a bilirrubina (produto da conversÃo de BVD pela enzima BVD redutase) foi entÃo dosada no lavado peritoneal. Protocolo 2: No modelo de placa quente, os camundongos foram prÃ-tratados com hemina (0,3, 1, ou 3mg/Kg; s.c), DMDC (0,00025, 0,025 ou 2,5ÂMol/Kg; s.c) ou ZnPP-IX (1, 3 ou 9mg/Kg; s.c) e, apÃs 30, 60 e 90 min, foi medido o tempo de permanÃncia dos animais na placa quente (55ÂC). Protocolo 3: No modelo de edema de pata induzido por carragenina (Cg), ratos foram prÃ-tratados com etoricoxibe (0,1, 1 ou 10mg/Kg; i.p) 30 min antes de receber a injeÃÃo sub-plantar na pata traseira direita de Cg, ou 60 min antes com Hemina (0,3, 1, ou 3mg/Kg; s.c), DMDC (0,25, 2,5 ou 25ÂMol/Kg; s.c) ou ZnPP-IX (1, 3 ou 9mg/Kg; s.c). Realizou-se ainda no mesmo modelo a coadministraÃÃo de doses nÃo efetivas de etoricoxibe com hemina ou DMDC e de uma dose efetiva de etoricoxibe com ZnPP-IX. Em seguida, o edema da pata foi medido por meio de um pletismÃmetro 1, 2, 3 e 4 h apÃs 60 min da injeÃÃo de Cg. ApÃs 4 h da injeÃÃo de Cg, amostras de tecidos da pata foram coletadas para anÃlise imunohistoquÃmica com anticorpos anti-COX-2 e anti-HO-1. Resultados: Hemina ou DMDC reduziram (p<0,05) o nÃmero de contorÃÃes e o edema de pata na 3 h, enquanto que o ZnPP-IX potencializou (p<0,05) o efeito do Ãcido acÃtico aumentando (p<0,05) o nÃmero de contorÃÃes e o edema de pata na 3 h, intensificando a aÃÃo da Cg. A coadministraÃÃo de etoricoxibe com hemina ou DMDC reduziu (p<0,05) o nÃmero de contorÃÃes. A coadministraÃÃo de etoricoxibe com DMDC reduziu (p<0,05) o edema de pata na 3 h, o que nÃo foi observado de forma significativa (p>0,05) na co-administraÃÃo de etoricoxibe com hemina. Jà na coadministraÃÃo de etoricoxibe com ZnPP-IX, observou-se que o ZnPP-IX reduziu o efeito analgÃsico e antiedematogÃnico do etoricoxibe. Nos modelos de placa quente, a administraÃÃo de hemina, DMDC ou ZnPP-IX nÃo afetou o tempo de permanÃncia dos camundongos na placa. ConclusÃo: A via da HO-1/BVD/CO à ativada nos modelos de contorÃÃo por Ãcido acÃtico e edema de pata por Cg, mas parece nÃo participar na mediaÃÃo central da nocicepÃÃo. O efeito analgÃsico e antiedematogÃnico do etoricoxibe depende, pelo menos parcialmente, da participaÃÃo da via da HO-1/BVD/CO. / Introduction: Heme oxygenase-1 (HO-1) plays a preventive role in oxidative stress. In contrast, COX-2 is involved in the pathogenesis of many inflammatory diseases and COX-2 selective inhibition has been shown to be effective in reversing inflammation without gastric side effects. However, serious cardiovascular effects of some selective COX-2 inhibitors emerged from clinical studies. Purpose: To assess the interaction between heme oxygenase -1/ biliverdin/ carbon monoxide (HO-1/BVD/CO) and cyclooxygenase-2 (COX-2) pathways for nociception and inflammation control in rats and mice. Methods: Protocol 1: In the abdominal writhe model induced by acetic acid, mice were pretreated with etoricoxib (selective COX-2 inhibitor; 0.1, 1 or 10mg/Kg; i.p) or with HO-1/BVD/CO pathway modulators, knowingly: Hemin (substrate of HO-1/BVD/CO pathway; 0.3, 1 or 3mg/Kg; s.c), DMDC (CO donor; 0.00025, 0.025 or 2.5ÂMol/Kg; s.c) or ZnPP-IX (specific HO-1 inhibitor; 1, 3 or 9mg/Kg; s.c). Animals pretreated with etoricoxib or HO-1/BVD/CO pathway modulators received the acetic acid injection (i.p.) after 30 and 60 min, respectively. Next, the number of abdominal contortions was quantified. In the same model, ineffective doses of etoricoxib were coadministered with hemin or DMDC and an effective dose of etoricoxib with ZnPP-IX. Four hours after the acetic acid injection, bilirubin levels (product of BVD conversion by the BVD reductase enzyme) were diagnosed in the peritoneal lavage. Protocol 2: In the hot-plate model, mice were pretreated with hemin (0.3, 1 or 3mg/Kg; s.c), DMDC (0.00025, 0.025 or 2.5ÂMol/Kg; s.c) or ZnPP-IX (1, 3 or 9mg/Kg; s.c) and, after 30, 60 and 90 min, the animalsâ response latency on the hot plate (55ÂC) was measured. Protocol 3: In the paw edema model induced by carrageenin (Cg), rats were pretreated with etoricoxib (0.1, 1 or 10mg/Kg; i.p) 30 min before receiving the subplantar injection of Cg in the right back paw, or 60 min before receiving injections with Hemin (0.3, 1 or 3mg/Kg; s.c), DMDC (0.25, 2.5 or 25ÂMol/Kg; s.c) or ZnPP-IX (1, 3 or 9mg/Kg; s.c). In the same model, ineffective doses of etoricoxib were coadministered with hemin or DMDC and an effective dose of etoricoxib with ZnPP-IX. Next, the paw edema was measured with a plethysmometer 1, 2, 3 and 4 h at 60 min after the Cg injection. Four hours after the Cg injection, paw tissue samples were collected for immunohistochemical analysis with anti-COX-2 and anti-HO-1 antibodies. Results: Hemin or DMDC reduced (p<0.05) the number of writhes and the paw edema in the 3rd h, while ZnPP-IX potentiated (p<0.05) the effect of acetic acid by increasing (p<0.05) the number of writhes and the paw edema in the 3rd h, intensifying Cg action. The coadministration of etoricoxib with hemin or DMDC reduced (p<0.05) the number of writhes. Coadministration of etoricoxib with DMDC reduced (p<0.05) the paw edema in the 3rd h, which was not significantly observed (p>0.05) when etoricoxib was coadministered with hemin. When etoricoxib was coadministered with ZnPP-IX, it was observed that ZnPP-IX reduced the analgesic and antiedematogenic effects of etoricoxib. In the hot-plate model, hemin, DMDC or ZnPP-IX administration did not affect the miceâs response latency on the plate. Conclusion: The HO-1/BVD/CO pathway is activated in the abdominal writhe model induced by acetic acid and paw edema by Cg, but does not seem to participate in the central mediation of nociception. The analgesic and antiedematogenic effect of etoricoxib at least partially depends on the participation of the HO-1/BVD/CO pathway.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

Made available in DSpace on 2016-01-26T12:51:42Z (GMT). No. of bitstreams: 1 rosasoubhia_tese.pdf: 792706 bytes, checksum: bba71696e22270729d09c3130cc047eb (MD5) Previous issue date: 2005-05-25 / Introduction: Tacrolimus (FK 506) is a potent immunosuppressive drug that may cause nephrotoxicity decreasing the renal blood flow (RBF) and glomerular filtration rate (GFR). Conventional non-steroidal anti-inflammatory drugs (NSAIDs) may cause nephrotoxicity, interfering with renal hemodynamics and fluid and eletrolyte homeostasis. Recently, new selective COX-2 inhibitors have been developed producing less side effects (gastric, cardiac and renal) related to COX-1 inhibition. The increasing use of FK 506 and the intensive use of NSAIDs with analgesic or ani-inflammatory purposes, increases the possibility of a drug combination, potentiating the nephrotoxic risk of the two drugs. Objective : Compare the renal function of rats receiving combination therapy with FK and a non-selective COX inhibitor, sodium diclofenac (SD) with those receiving FK and a selective COX-2 inhibitor, rofecoxib (RO). Material and Methods : Male Munich-Wistar rats receiving a low sodium diet (0.06%) for 7 days and gavage treatment for 7 days with FK (2 mg/kg/day), SD (10 mg/kg/day), RO (3 mg/kg/day), FK+SD, FK+RO and vehicle (control) were used. Glomerular filtration rate (GFR, inulin clearance, ml/min/100g); renal blood flow (RBF, Doppler ultrasound, ml/min); mean blood pressure (MBP, intracarotid probe, mmHg); renal vascular resistence ( RVR, mmHg/ml/min); hematocrit (Htc); urinary volume ( UV, &#956;l/min); solute clearance; renal histology; animal weight (g) and FK serum concentration (SCFK, ng/ml) were assessed. Results are presented as a mean±standart deviation and compared by ANOVA followed by Student-Neuman-Keuls test. Results : The GRF of the SD group was 0.98±0.03, RO 1.06±0.04 and FK 0.99±0.06 similar to control values (1.10±0.05). GRF values decreased in the FK+RO (0.86±0.06;p<0.05 vs RO and Control) and FK+SD (0.63±0.06;p<0.001 vs control, FK and SD groups and p<0.01 vs FK+RO) groups. RBF, MBP, RVR and Htc values were similar in all groups. Diuresis was lower in the groups with drug combination, but there was a statistically significant difference only between FK+SD and RO groups (8.38±0.46 vs 12.99±1.22;p<0.05). There were no significant histological chan ges in the treatment groups. The FK+SD group showed statistically significant weigth changes (-18±5) when compared to the Control and RO groups (6±2 and 5±2, respectively; p<0.001) and to the SD an FK+RO groups (0.2±4 and 1±2, respectively; p<0.01). SCFK was significantly decreased (p<0.05) for FK+SD and FK+RO (1.7±0.3 and 1.8±0.4) groups when compared to the FK group (3.2±0.4. Conclusions: The combination of FK and a non-selective COX inhibitor significantly decreased GFR regardless of a RBF decrease or RVR increase, and is probably a result of Kf decrease. The trend to antidiuresis was similar for the combination of FK with both classes of NSAIDs. FK combined to a non-selective COX inhibitor caused a mild systemic toxicity when compared with the COX-2 selective inhibitor. Serum FK concentrations were significantly lower in NSAIDs treated animals. / Introdução: O tacrolimus (FK 506) é uma potente droga imunossupressora, pode causar nefrotoxicidade aguda com diminuição do fluxo sanguíneo renal (FSR) e ritmo de filtração glomerular (RFG). Os antiinflamatórios não-hormonais (AINHs) convencionais podem causar nefrotoxicidade, interferindo na hemodinâmica renal e na homeostase de fluidos e eletrólitos. Recentemente surgiram novas drogas do grupo coxib que são inibidores seletivos da COX-2, e portanto teriam menos efeitos colaterais relacionados à inibição da COX-1 (gástricos, cardíacos e renais). O crescente uso do FK 506 e o intenso uso de AINHs com finalidade analgésica e ou antiinflamatória aumenta a possibilidade de utilização em conjunto, potencializando o risco de nefrotoxicidade das duas drogas. Objetivo: Comparar a função renal de ratos sob os efeitos do uso simultâneo do FK e de um inibidor não-seletivo da COX, o diclofenaco sódico (DS) e do FK e de um inibidor seletivo da COX-2, o rofecoxib (RO). Materiais e Método: Utilizaram-se ratos Munich-Wistar machos em dieta hipossódica (0,06%) por 7 dias e tratamento por gavagem por 7 dias com FK (2 mg/kg/dia), DS (l0mg/kg/dia), RO (3mg/kg/dia), FK+DS, FK+RO e veículo (Contr). Aferidos ritmo de filtração glomerular (RFG, depuração de inulina, ml/min/l00g); o fluxo sanguíneo renal (FSR, ultrasom Doppler, ml/min); a pressão arterial média (PAM, probe intracarotídeo, mmHg); a resistência vascular renal (RVR, mmHg/ml/min); hematócríto (Ht); o volume urinário (VU, pl/min); a depuração de solutos; a histologia renal; o peso dos animais (g) e a concentração sanguínea de FK CSFK, ng/ml). Os resultados são apresentados com médiaserro padrão da média e comparados por ANOVA seguido do teste Student-Neuman-Keuls. Resultados: O RFG do grupo DS foi 0,980,03, do RO foi 1,060,04 e do FK 0,990,06 similares ao controle (1,100,05). Houve queda do RFG nos grupos FK+RO (0,860,06;p<0,Os vs RO e Contr) e FK+DS (0,630,06;p<0,001 vs Contr,DS, RO e FK; p<0,01 vs FK+RO) Nota de Resumo O FSR, a PAM, a RVR e o Ht foram semelhantes em todos os grupos. A diurese foi menor nos grupos com associação de drogas, mas houve diferença estatisticamente significante apenas entre os grupos FK+DS e RO (8,380,46 vs l299l,22;p<0,05). Não ocorreram modificações histológicas significativas nos grupos estudados. O grupo FK+DS apresentou variação de peso (-185) estatisticamente significante em relação aos grupos Contr 62 e RO 52 (p<0,001) e DS 0,24 e FK+RO -12 (p<0,01). A CSFK diminuiu significativamente (p<0,05) para os grupos FK+DS e FK+RO (1,70,3 e 1,80,4) em relação ao grupo FK (3,20,4). Conclusões: A associação do FK com um inibidor não-seletivo da COX causou diminuição mais acentuada do RFG independentemente da diminuição do FSR ou aumento da RVR, sendo provavelmente decorrente da diminuição do Kf. A tendência à antidiurese foi similar para a associação do FK com as duas classes de AINHs. O FK associado com um inibidor não-seletivo da COX causou discreta toxicidade sistêmica quando comparado com inibidor seletivo da COX-2. Nos animais tratados com AINHs, as concentrações sanguíneas do FK foram significativamente menores.