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Efeito dos imunossupressores ciclosporina microemulsão, micofenolato mofetil e rapamicina no desenvolvimento do tumor de Walker

Wed, 01 Jan 2003 00:00:00 GMT

Título: Efeito dos imunossupressores ciclosporina microemulsão, micofenolato mofetil e rapamicina no desenvolvimento do tumor de Walker Autor(es): Silva, Sonia Leite da Abstract: Purpose: The purpose of this study was to investigate the effect of 3 immunosupressive drugs on Walker's tumor development and to evaluate a novel isolation technique of these tumoral cells using a ficoll-hypaque gradient. Methods and Results, one million of tumoral cells were inoculated by sc. injection in the right axilary region in forty male Wistar rats, 4-8 weeks-age. Tumor volume (TV), % tumor growth/inhibition (Tl), and tumor weight (TW) were assessed and analysed by ANOVA multivariate and univariate assays. Experiment I: 1-Control (n=10), mineral water; 2-Rapamycin, 1.5mg/kg/day (Rapa, n=10); 3-Cyclosporin microemulsion, 10mg/kg/d, (CsA, n=10); 4-Mycophenolate mofetil, 10mg/kg/d (MMF, n=10). All drugs were introduced one day before tumor inoculation and administered p.o. over 10 days. On day 10, TV was smaller in Rapa than in Control (6.8±2.7cm3 vs. 14.9±4.2cm3, p<0.001) in opposition to CsA (13.9±3.0cm3, p=0.89). TV was lower in MMF than in Control (10.3±2.8cm3, p<0.05) and similar to CsA and Rapa Tl was -49.3% in Rapa and -28.3% in MMF. TW was also significantly lower in Rapa (3.7±1.2g), MMF (5.2±2.0g) as compared to CsA (8.8±2.1g) and Control (7.3±2.0g). Experiment II: Control (n=9); Rapa (n=8); Rapa+CsA (n=9); Rapa+MMF (n=9). All drugs were started 24 hr. before tumor inoculation and adiministered over 10 days. On day 10, TV was lower in Rapa, Rapa+CsA and Rapa+MMF as compared to Control (3.8±1.5cm3; 3.1±1.2cm3 and 4.6±2.7cm3 vs. 10.9±3.8cm ; p<0.0001). TW was also lower in theses groups than in Control (3.5±1.2g; 2.3±0.4g; and 2.7±1.1g vs. 7.3±1.4g; p<0.0001). Tl was -52.1% in Rapa, -68.5% in Rapa+CsA and -63% in Rapa+MMF. Experiment III: Control (n=7); CsA (n=9); MMF+CsA (n=8). Drugs were given p. o. over 10 days beginning 24 hr. before tumor inoculation. On day 10, TV was similar (p=0.435) in MMF+CsA (19.7±3.7cm3) as compared to CsA (18.3±3.4cmá) and Control (19.1±3.5cm''). TW was similar in theses groups (CsA=11.2±2.1g; MMF+CsA=9.9±2.8g; and Control=9.7±3.1g; p=0.457). Experiment IV: Control (n=7); Rapa (n=10); MMF (n=9). All drugs were started on Day 4 after tumor implant and administered over 7 days. On day 10, TV in Rapa and MMF were similar to Control (Rapa=13.2±3.2cm3and MMF=12.3±5.5cm3vs Control=14.9±7.4cm3; p=0.831) as well as TW (Rapa=5.2±1.6g and MMF=6.9±2.4g vs. Control=6.3±3.2g; p=0.229). Experiment V: Isolation Technique of Tumoral cells Using a Ficoll-Hvpaaue Gradient. The tumoral cells were centrifuged on a Ficolt-Hypaque gradient and one million cells tumoral were implanted in the right axilary region (n=10) and TV, Tl, and TW were compared with technique without the Ficoll-Hypaque gradient (n=10). On day 10, no differences were observed in TV (without ficoll=17.9±3.8 and with ficoll=17.214.4cm ; p=0.190) and TW (without ficoll=7.0±1.8g; with ficoll =7.3±2.8g, p=0.569). Experiment VI: the effect of Rapa on tumor growth was assessed using the tumor cell suspension obtained by a ficoll-hypaque gradient. Control (n=10) olive oil; Rapa (n=10). Treatment was started on Day 4 after tumor implant and administered p. o. over 10 days. On day 13, TV in Rapa (21.1 ±6.0 cm3) was similar to Control (24.9±6.4cm3; p=0.831). as well as TW on day 14 (Rapa=9.3±4.0g vs. Control=10.0±2.6g; p=0.445). Conclusions: A Ficoll-Hypaque gradient can provide more adequate isolation of Walker's carcinossarcoma cells. Rapamycin greatly inhibited tumor growth when used alone or in association with cyclosporin micro-emulsion or MMF. MMF when used alone in this model attenuated Walker's carcinossarcoma growth but this inhibitory effect was lost when MMF is used in combination with CsA. There was no synergism in the association Rapa + MMF in the inhibition of tumor growth The antiproliferative effect of Rapa or MMF was lost when either drug was administered in presence of a established tumor. Tipo: Tese

Participação de mastócitos e mediadores pró-inflamatórios na patogênese das enterotoxinas do Vibrio cholerae e Bacteroides fragilis

Tue, 01 Jan 2002 00:00:00 GMT

Título: Participação de mastócitos e mediadores pró-inflamatórios na patogênese das enterotoxinas do Vibrio cholerae e Bacteroides fragilis Autor(es): Costa, Raimundo Bezerra da Abstract: This work deals with Vibrio cholerae and Bacteroides fragilis toxins, aiming to investigate the pharmacodynamics of their enterotoxic and proinflammatory activities. Cholera toxin caused dose-dependent secretory response in ligated loops of rat intestine. Rats treated with 48/80 compound or ketotifen showed a significant decrease in intestinal secretory response evoked by cholera toxin (blocking: 45% and 52%, respectively to 48/80 and ketotifen). Such secretory response was also significantly reduced by histamine/serotonine receptors antagonists (cyproheptadine: 48%), histamine (diphenhydramine: 45%), phospholipase Â2 inhibitors (dexamethasone: 43% and quinacrine: 35%), cyclooxygenase blockers (celocoxib: 60% and meloxican: 71%), PAF receptors antagonists (BN 52021: 32% and WEB 2086: 32%) and TNF-a synthesis inhibitors (pentoxifyline: 62% and thatidomide: 44%). On the other hand, the previous treatment with serotonine receptor specific antagonist and lipooxygenase inhibitors failed to inhibit this effect. ELISA trials of intestinal fluid derived from rats submitted to cholera toxin demonstrated that this toxin induced IL-1p and TNF-a release at intestinal fluid. Histopathology examination of intestinal tissue, 18h after toxin injection of loop, revealed hemodynamic disturbances such as congestion and edema of mucosal/submucosal layers, besides a severe infiltration of mast ceils at the intestinal corion. Intraluminal injection of culture supernatants from non toxigenic and toxigenic strains, as well as from purified toxin of 6. fragilis, was not able to induce significant intestinal secretion. However, structural changes were seen in the shape of villi and crypts, plus submucosal and mucosal layers modifications, including the occurrence of severe mast cell infiltration. In addition, some other vital organs exhibited morphological changes such as liver, heart, kidneys and brain. Cell migration, which was induced by B. fragilis purified toxin, was associated with a significant increase in number of mast cells (TBFspg/mi: 0,450 ± 0,050 vs. PBS: 0,200 ± 0,037; 4 h) and eosinophils (TBFspg/mi: 0,750 ±0,157 vs. PBS: 0,367 ± 0,126; 4h; and TBF3pg/mi: 0,800 ± 0,115 vs. PBS: 0,433 ± 0,084; 8h). xxiii On the contrary, B. fragilis purified toxin was not able to induce neutrophil or mononuclear cell migration. Our results suggest that the secretory response to cholera toxin involves an inflammatory reaction orchestrated by mast cells, histamine, prostaglandins, PAF, IL-1p and TNF-a. B. fragilistoxïn promoted mast cells and eosinophils migration, in vivo. This seems to reveal an efficient pro inflammatory participation on biological activities of \/. cholerae and B. fragilis toxins. Tipo: Tese

Avaliação eletrofisiológica da ação dos antioxidantes glutation e ácido alfalipóico em um modelo animal de isquemia cerebral

Sat, 01 Jan 2000 00:00:00 GMT

Título: Avaliação eletrofisiológica da ação dos antioxidantes glutation e ácido alfalipóico em um modelo animal de isquemia cerebral Autor(es): Vale, Otoni Cardoso do Abstract: An animal model for brain ischemia was developed. An electroencephalographic analysis of several band fi'equency absolute amplitudes has been performed m order to demonstrate the effects on cerebral electric activity induced by ischemia, followmg common carotid arteries büateral obüteration in Wistar-Kyoto rats, anaesthetized with urethane. The waves were recorded fi-om subcutaneous electi-odes on left frontal (F3), right frontal (F4), left parietal (P3), right parietal (P4) and vertex (Cz) regions. This electi-ophysiological analysis consisted of the absolute amplitude means evaluation of the several frequency spectra (alpha, betai, betaz, betas, theta and delta). The cerebral electrical activity was picked up by an appropriate hardware and a software system for analysis. It has been verified a highly significant reduction of the absolute amplitude means of the spectrum waves (P<0,015) after both common carotid arteries occlusion. The miusion of 1.2 mM reduced glutathione solution into the cephalic segment of the left common carotid artery of Wistar-Kyoto rats significantly reverted the depression of the absolute amplitudes of the several spectral frequencies of the electroencephalogram (P<0,05) induced by obüteration of both common carotid arteries. The infusion of 0,12 mM reduced glutafhione or saline solution into the cephalic segment of the left common carotid artery of the same animals did not reverted significantly the depression oftiie electroencephalographic wave absolute amplitudes mduced by obuteration of both common carotid arteries. The occlusion of left common carotid artery in urethane anaesthetized Wistar-Kyoto rats caused less significant absolute amplitude reduction than both carotid arteries occlusion and the the absolute amplitude recovery with intracarotid 1,2 mM reduced glutathione infusion was less evident. The left intracarotid infusion of 0,12 mM reduced glutathione m rats with bilateral common 281 carotid arteries occlusion reverted the ischemic absolute amplitude reduction of only right frontal betai hypersynchronic activity (P<0,05), but induced NREM sleep electi'ophysiological activity (P<0,05). The intracarotid infusion of 2,1 mM L-cystine or 1,2 mM L-glutanüne in rats wiüi both common carotid arteries occlusion did not cause consistent absolute amplitude modifications of the electoencephalographic spectral waves. The inti'acarotid infusion of 3,03 mM a-1ipoic acid in rats with both common carotid arteries occlusion caused initial reduction and partial final absolute amplitude recuperation of several specti-al band fi-equencies (P<0,05); the mtracarotid infusion of 6,06 mM a-1ipoic acid significantly reverted the ischemic depression of the absolute amplitudes of frontal theta and right parietal delta spectra; the mtracarotid infusion of 60,6 mM a-1ipoic acid significantly increased Uie absolute amplitude ischemic-mduced depression of ahnost all specti-al electroencephalographic waves (P<0,05). Fmally, It has been demonstrated that intracarotid 1,2 mM reduced glutathione and 6,06 mM a-1ipoic acid m rats with both common carotid arteries occlusion increased the inu-acerebral level of reduced glutathione (P<0,05). It was concluded that an appropriated electroencephalographic analysis of Wistar-Kyoto rats with both carotid arteries occlusion is a valuable study model of cytotoxic effects of cerebral ischemia and could be used to verify fhe cytoprotector reduced glutathione effect and both pro-oxidant and oxidant a-1ipoic acid action, as weU as other drug effect studies Tipo: Tese

Alternativas terapêuticas na prevenção da cistite hemorrágica induzida por Ciclofosfamida e Ifosfamida com drogas antiinflamatórias: um estudo experimental comparativo com o Mesna

Sat, 01 Jan 2000 00:00:00 GMT

Título: Alternativas terapêuticas na prevenção da cistite hemorrágica induzida por Ciclofosfamida e Ifosfamida com drogas antiinflamatórias: um estudo experimental comparativo com o Mesna Autor(es): Morais, Milena Maia de Abstract: Hemorrhagic cystitis (HC) is a therapy-limiting side effect of antineoplastic agents such as cyclophosphamide (CYP) and ifosfamide (IFS). Mesna is the drug of choice to prevent HC. Previous data, from the Laboratory of Pharmacology of Inflammation and Câncer, of Federal University of Ceará, have demonstrated that nitric oxide, platelet-activating factor and cytokines, like tumor necrosis factor alpha and interleukin-1 are crucial mediators involved in inflammatory events of HC, as well as in the urothelial damage and hemorrhage. Thus, the present study aimed to evaluate the effects of antiinflammatory drugs (AID), such as glucocorticoids (dexamethasone), selective ciclooxigenase 1 and 2 inhibitors (indomethacin and meloxicam, respectively) and natural products, such as Myracrodruon urundeuva Fr.AII. (Aroeira do Sertão), Ageratum conyzoides L. (Mentrasto) and ternatin, a flavonoid isolated from Egletes viscosa Less. (Macela), for the prevention of CYP- and IFS- induced HC. For this, male Wistar rats (150-200 g; n=6 per group) were treated with saline or mesna immediately and 4 and 8 hours, or 2 and 6 hours after administration of CYP or ÍFS. In other experimental groups, 1, 2 or 3 doses of mesna were replaced with AID, or the last two doses of mesna were replaced with saline or with the association (mesna+dexamethasone). 24 h after de administration of CYP or IFS, HC was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP and IFS treatment induced a marked increase in BWW, which was significantly (p<0.05) inhibited by treatment with 3 doses of mesna, and also by the replacement of 2a or 3a doses of mesna with AID. The replacement of the last two doses of mesna with the association (mesna+dexamethasone) promoted a marked inhibition of the increased in BWW induced by IFS. Macroscopic analysis of the bladder of rats with CYP- or IFS-induced HC showed severe edema and hemorrhage and microscopic analysis showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 2a or 3“ doses of mesna with AID or the replacement of the last two doses of mesna with the association (mesna+dexamethasone) almost abolished the macroscopic and microscopic alterations. However, the replacement of 3 doses of mesna with AID or the replacement of the last two doses of mesna with saline, did not prevent HC. In conclusion, the replacement of the last two doses of mesna with AID or with the association (mesna+dexamethasone) could be therapeutic alternatives, if they were clinically tested for the prevention of CYP- or IFS- induced HC, however, mesna is necessary for the initial uroprotection. Tipo: Dissertação