No description available.

Thèse d'exercice : Médecine vétérinaire : Toulouse 3 : 2008. / Titre provenant de l'écran titre. Bibliogr. f.45-49.

Chronic lung diseases are often complicated with pulmonary hypertension (PH). This can lead to disability and poor prognosis. Oxidative stress has been implicated in the development of PH and right ventricular hypertrophy (RVH).A possible new way to treat lung disease related pulmonary hypertension is allopurinol (a xanthine oxidase inhibitor) which decreases both uric acid and oxidative stress. We hypothesised that allopurinol could regress RVH in patients with pulmonary hypertension associated with chronic lung disease (PH-CLD).In a double-blind, randomised controlled clinical trial, 72 patients with PH-CLD (93% diagnosed with chronic obstructive pulmonary disease and 17% with interstitial lung disease) were randomised to receive either allopurinol 300 mg twice daily or placebo for twelve months. The primary outcome was the mean change in right ventricular mass (RVM) as assessed by cardiac magnetic resonance imaging (CMRI) at twelve months. The secondary outcomes were the change in other cardiac parameters measured by CMRI, St George's Respiratory Questionnaire, Short Form 36, spirometry and six-minute walk test (6MWT).The mean age was 71 years, the mean FEV1 was 60% with mean resting SaO2 of 96%. After 12 months, there was no significant change in RVM. There were also no significant changes in other cardiac parameters measured on CMRI, quality of life questionnaires, spirometry and 6MWT. Post-hoc subgroup analysis showed that allopurinol reduced RVM (allopurinol -6.16 g vs placebo 0.75 g, p = 0.02) in COPD patients with more severe airflow limitation. Patients with higher NT-proBNP (> 489 pg/ml) had a greater improvement in left ventricular ejection fraction with allopurinol 5.12 vs placebo -1.62, p = 0.02.In summary, allopurinol had no overall impact but reduced RV mass in COPD patients with more severe airflow limitation. Further studies are warranted to assess the longer term impact of allopurinol in more severe COPD.

Left Ventricular Hypertrophy (LVH) is common in Type 2 Diabetes (T2DM) and despite optimal treatment of blood pressure can still persist. We know LVH is a cardiovascular (CV) risk factor in its own right and contributes to high CV event rates in patients with T2DM. Apart from hypertension, other factors contribute to the development of LVH in patients with T2DM, in particular oxidative stress (OS) has been implicated in LVH development. Allopurinol is a potent anti-oxidant, acting by blocking the enzyme Xanthine Oxidase, and has been previously shown to reduce vascular OS. Therefore the main aim of this thesis was to investigate whether allopurinol regresses LVH in patients with T2DM. The trial design was a randomised, double blind, placebo controlled study in 66 patients with T2DM with echocardiographic evidence of LVH. Allopurinol 600mg/day or placebo was given for nine months over the study period. The primary outcome was reduction in left ventricular mass (LVM) as calculated by cardiac magnetic resonance imaging (CMR) at baseline and at nine months follow-up. The secondary end-points were change in flow mediated dilatation (FMD) and augmentation index (AIx). Allopurinol significantly reduced absolute LVM (-2.65 ± 5.91g and placebo group +1.21 ± 5.10g (p=0.012)) and LVM indexed to body surface area (-1.32 ± 2.84g/m2 and placebo group +0.65 ± 3.07g/m2 (p=0.017)). When analysis was made of high and low baseline LVM then the effects of allopurinol were exaggerated in the high LVM mass group. No significant change was seen in either FMD or AIx. This thesis shows that allopurinol regresses LVM in patients with T2DM and LVH and controlled blood pressure. Regressing LVH has been shown previously to improve CV mortality and morbidity. Therefore allopurinol may become a useful therapy to reduce CV events in T2DM patients with LVH.

Universiẗat, Diss.--Heidelberg, 1997.

Patients with peripheral arterial disease (PAD) can only walk so far before they get leg pain (intermittent claudication) and have to stop. They are also at risk in the future of needing amputation of one of their limbs. Allopurinol is a new possible treatment for this condition as it has been shown in coronary arterial disease to prolong exercise before angina pain occurs. This is thought to be because allopurinol can both prevent oxygen wastage in tissues and prevent the formation of harmful oxidative stress. We hypothesised that allopurinol could prolong the time to leg pain in participants with PAD. In a double-blind, randomised controlled clinical trial 50 participants with PAD were randomised to receive either allopurinol 300mg twice daily or placebo for six months. The primary outcome was change in exercise capacity on treadmill testing at six months. Secondary outcomes were six-minute walking distance, Walking Impairment Questionnaire, SF-36 QoL questionnaire, flow-mediated dilatation and oxidised LDL. Outcome measures were repeated mid-study and at end of study. The mean age of participants was 68.4 years (SD 1.2) with 39/50 (78%) male. Only five participants withdrew in the course of the study, two in the active group and three in the placebo group. There was a significant reduction in uric acid levels in those on active treatment of 52.1% (p<0.001), but no significant change in either the pain-free or the maximum distance they were able to walk. Other measures of exercise capacity, blood vessel function and the participants’ own assessment of their health and walking ability also did not change during the course of the study. In summary, although allopurinol has been shown to be of benefit in a number of other diseases, in this study there was no evidence of any improvement following treatment in patients with peripheral arterial disease.

A growing body of evidence has now accumulated supporting the involvement of oxygen-derived free radicals in the development of myocardial ischemia/reperfusion (I/R) injury. We have, therefore, undertaken the present study to examine (1) I/R-related alterations in myocardial antioxidant capacity in pentobarbital anesthetized open-chest rabbits subjected to left circumflex coronary artery ligation followed by reperfusion; (2) the protective effects of pretreatrnent with allopurinol or the 21-aminosteroid U74006F; (3) alternative mechanisms to xanthine oxidase inhibition for allopurinol protection against I/R injury; and (4) the effect of allopurinol treatment on the antioxidant capacity of erythrocytes in pigs used in a heart-lung transplantation study. In the rabbit myocardium, a marked impairment in myocardial antioxidant capacity developed in association with the onset of irreversible injury, as reflected in the enhancement in glutathione (GSH) depletion and formation of thiobarbituric acid-reactive substances (TBARS) following in vitro incubation of tissue homogenate with tert-butylhydroperoxide (TBHP). During the course of post-ischemic reperfusion, the protracted time-course of alterations in antioxidant capacity dissociated them from the early burst of radical formation known to occur at the onset of post-ischemic reperfusion of the myocardium. When the time-dependent changes in functional indices of antioxidant status (TBHP-induced GSH depletion and formation of TBARS) were analysed in relation to activities of antioxidant enzymes, evidence suggestive of functionally relevant impairments in Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and glutathione reductase (GRD) activities was found. These results and our demonstration of significant decreases in the activity of GSH-dependent antioxidant enzymes under acidotic conditions suggest that a transient impairment in the functioning of antioxidant enzymes may be involved in triggering irreversible myocardial I/R injury. Repetitive brief episodes of I/R produced a progressive decrease in myocardial ATP levels, which was not associated with any detectable changes in myocardial antioxidant capacity. Ischemic preconditioning produced by brief episodes of I/R did not affect the severity of subsequently induced I/R injury. These results suggest that brief episodes of myocardial ischemia do not produce oxidative tissue damage and the ischemia-induced depletion in myocardial ATP level is at least partially dissociable from the I/R-related impairment in tissue antioxidant capacity. Isolated Langendorff-perfused rabbit hearts subjected to I/R did not show any changes in antioxidant capacity. However, when intact hearts were subjected to ischemia in vivo and a subsequent reperfusion in vitro, an impairment in myocardial antioxidant capacity became apparent. These results suggest that blood elements, possibly activated neutrophils, may be a crucial factor involved in the development of I/R-induced oxidant injury. Chronic allopurinol pretreatment (1 mg/ml in drinking water or approximately 75 mg/kg/day) for 7 days prior to ischemia provided significant protection against I/R-induced alterations in myocardial antioxidant capacity, but not the decrease in tissue ATP levels. This chronic allopurinol regimen was found to enhance myocardial GRD activity in nonischemic tissue. In addition, both allopurinol and oxypurinol inhibited the transition metal ion-catalysed ascorbate oxidation and lipid peroxidation in vitro, likely as a consequence of their metal chelating properties. Similarly, myoglobin-TBHP-catalysed oxidation of uric acid and lipid peroxidation were also suppressed by allopurinol. All these suggest that allopurinol may favorably alter myocardial antioxidant capacity directly by virtue of its transition metal chelating properties and its antioxidant actions in myoglobin-mediated oxidative processes. The acute administration of 21-aminosteroid U74006F (3 mg/kg, i.v) under conditions comparable to those known to protect against trauma-induced damage in the central nervous system failed to reduce manifestations of oxidative injury in rabbit hearts subjected to ischemia and reperfusion. Although reactive oxy-radicals have been implicated in both types of tissue damage, the observed difference in susceptibility to protection by this steroidal antioxidant suggests that the molecular mechanisms involved are not identical. In the heart-lung transplantation study, erythrocytes from allopurinol-treated pigs (given repeatedly at an oral dose of 50 mg/kg) showed a time/dose-dependent increase in antioxidant capacity as reflected in the decrease in malondialdehyde production following in vitro oxidative challenge. The extent of red cell protection in both donor and recipient animals correlated significantly with the functional viability of the transplanted lung tissue, as assessed by tissue water content. These results suggest that the measurement of erythrocyte antioxidant capacity may provide an useful assessment of generalized alterations in tissue antioxidant status produced by pharmacological interventions. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Existe uma relação entre o uso abrangente de inibidores da bomba de prótons (IBPs), como o omeprazol, e o aumento de risco cardiovascular. Essa relação está associada ao efeito dos IBPs de interferir na síntese e biodisponibilidade do óxido nítrico (NO), um fator importante na homeostase vascular. Também foi evidenciado que o omeprazol causa disfunção endotelial junto a um desequilíbrio redox em aortas, mediado pela ativação da enzima xantina oxidoredutase (XOR), responsável pelo catabolismo das purinas e geração de espécies reativas de oxigênio (ERO). As ERO decorrentes da atividade da XOR, podem aumentar a expressão e a atividade de metaloproteinases de matriz (MMPs), principalmente a MMP-2, que são promotoras de remodelamento tecidual. Assim, nosso objetivo foi analisar se o omeprazol causa remodelamento vascular em aorta de ratos, frente ao seu efeito de aumento do estresse oxidativo via XOR promovendo ativação de MMPs. Foram utilizados ratos wistar com peso entre 180-200 g (n=40), separados em 4 grupos de tratamento onde cada animal foi tratado com 0,5 mL de solução das drogas nas seguintes especificações: o grupo Controle (C) foi tratado com solução veículo tween 2% (vol./vol.) 1 vez ao dia por gavagem, o grupo Alopurinol (A) recebeu uma solução deste inibidor de XOR por gavagem (50 mg/kg/dia), o grupo Omeprazol (O) que recebeu uma solução de omeprazol diluída em tween 2% por via intraperitoneal (10 mg/kg/dia) e por fim, o grupo Omeprazol+Alopurinol (O+A) que recebeu as duas drogas concomitantemente. O protocolo experimental durou 4 semanas, durante as quais foram realizadas aferições da pressão arterial sistólica por pletismografia de cauda. Ao fim do tratamento, os animais foram submetidos à eutanásia, onde foi aferido o pH do lavado gástrico e foi coletada a aorta torácica para a análise de reatividade vascular, análise bioquímica de ERO, a análise morfométrica, e ensaio de atividade de MMPs. Não houve variação de pressão arterial em nenhum dos grupos. O tratamento com alopurinol não alterou nenhum dos parâmetros analisados em relação ao grupo controle neste estudo. O pH gástrico aumentou nos grupos tratados com omeprazol. Na reatividade vascular, observamos que o omeprazol diminuiu o efeito máximo da resposta vasodilatadora dos anéis de aorta à acetilcolina, mas que o tratamento associado ao alopurinol (O+A) preveniu essa diminuição. Em relação ao pD2, foi constatado que o tratamento com omeprazol resulta na diminuição da potência da acetilcolina em causar relaxamento vascular, e que a associação do tratamento com alopurinol, não foi capaz de prevenir essa diminuição. O grupo O também apresentou aumento de espécies reativas de oxigênio no leito vascular, observados no ensaio DHE e o tratamento com alopurinol preveniu este efeito. No ensaio de atividade gelatinolítica in situ observamos um aumento da atividade de MMPs no grupo O, e o tratamento com alopurinol também preveniu esse efeito. Na análise morfométrica observamos que o grupo O apresentou aumento dos parâmetros de remodelamento vascular, denotando um remodelamento hipertrófico, que foi prevenido pela associação com alopurinol. Com base nos resultados, é possível concluir que o tratamento com omeprazol causou remodelamento em aortas de ratos, e que esse efeito ocorreu paralelamente a outros prejuízos, como a diminuição da função vascular avaliada pela resposta à acetilcolina, aumento de espécies reativas de oxigênio e aumento de atividade de MMPs. Como todos esses efeitos resultantes do uso do omeprazol foram prevenidos pela associação do tratamento com alopurinol, é viável inferir que a XOR participe da via pela qual o omeprazol causa efeitos deletérios sobre a vasculatura / There is a relationship between the use of proton pump inhibitors (PPIs), such as omeprazole, and the increase of cardiovascular risk. This relation is associated with the effect of PPIs on nitric oxide synthesis and bioavailability, which is an important factor to vascular homeostasis. It also clear that omeprazole causes endothelial dysfunction by mechanisms involving xanthine oxidoreductase (XOR) mediated redox imbalance in aortas, which is responsible for purines catabolism, and generates reactive oxygen species (ROS). ROS derived from XOR activity, may increase matrix metalloproteinases expression and activity, mainly MMP-2 that are promoters of tissue remodeling. Thus, our aim was to analyze if omeprazole entails vascular remodeling in rat\'s aorta, with its effect of causing oxidative stress via XOR, promoting MMPs activation. Male rats weighing between 180-200g (n=40) were assigned to 4 groups with different treatments, where each animal was treated with 0.5 mL of drug solution, following the specification per group: Control group (C) was treated with the vehicle tween 2% (vol./vol.) 1 time a day by gavage; Allopurinol group (A) that received a solution of this XOR inhibitor by gavage (50mg/kg/day), Omeprazole group (O) which was treated by intraperitoneal route with a solution of omeprazole diluted at tween 2% (10 mg/kg/day) and at last, the Omeprazole+Allopurinol group (O+A), that received both drugs concomitantly. The experimental protocol lasted 4 weeks, during which, were performed systolic blood pressure measurements by tail cuff plethysmography. By the end of treatments, the animals were submitted to euthanasia, then the pH of the gastric washing was measured, and the thoracic aorta was collected to study vascular reactivity, biochemical analysis of ROS, morphometric analysis and MMPs activity assay. There was no blood pressure variation in any of the treatment groups. Treatment with allopurinol did not alter any of the parameters that were analyzed in the present study, in comparison to control group. Gastric washing pH increased in groups treated with omeprazole. In vascular reactivity, it was noticed that omeprazole decreased the maximum effect of the aortic ring\'s vasodilator response to acetylcholine, while the omeprazole treatment associated with allopurinol (O+A) prevented this decrease. Regarding to pD2, it was observed that omeprazole treatment results in decreased acetylcholine potency to cause vascular relaxation, and the association to allopurinol treatment was not capable of preventing this decrease. The O group also presented increased reactive oxygen species levels in the vascular bed, according to DHE assay, and the treatment with allopurinol prevented this effect. With respect to in situ gelatinolytic activity assay, we noticed an increase in MMPs activity in the O group, and the treatment with allopurinol prevented that. The morphometric analysis showed the O group with increased vascular remodeling parameters, denoting a hypertrophic remodeling, which was prevented by the association with allopurinol. Based on these results, is possible to conclude that the treatment with omeprazole caused aortic remodeling in rats, and combined to this effect, some other were observed, such as the vascular function impairment evaluated by the response to acetylcholine, the increase of ROS and increase in MMPs activity. As the effects of omeprazole treatment were prevented by the association of treatment with allopurinol, it is reasonable to infer that XOR participates of the pathway by which omeprazole exerts its deleterious effects on the vasculature

Orientador: Marilda Mazzali / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-08T15:27:17Z (GMT). No. of bitstreams: 1 Mazali_FernandaCristina_M.pdf: 3384913 bytes, checksum: 0d3a47a884265f3d5949b9aff82161a6 (MD5) Previous issue date: 2006 / Resumo: Objetivo: Hiperuricemia é uma complicação freqüente da terapêutica com ciclosporina (CsA). Estudos anteriores demonstraram que a hiperuricemia exacerba a lesão intersticial e vascular no modelo experimental de nefrotoxicidade por CsA (CsA ntx). O presente estudo tem como hipótese que a normalização da uricemia preveniria o desenvolvimento da nefropatia crônica por CsA. Metodologia: A nefropatia crônica por CsA foi induzida em ratos machos, Sprague Dawley, através da injeção subcutânea diária de CsA (15mg/kg/dia), por um período de 7 semanas, em associação com dieta hipossódica (CSA). O efeito do controle da hiperuricemia foi determinado através do tratamento concomitante com um inibidor de xantina oxidase (alopurinol, 15mg/Kg/dia ? CSA/ALP) ou com um agente uricosúrico (benzbromarona, 15mg/Kg/dia, CSA/BENZ), em bebedouro. O grupo-controle incluiu ratos tratados com veículo (VEH, injeções SC diárias de óleo de oliva). Ao sacrifício foram realizadas análises funcionais e histológicas. Resultados: Os animais do grupo CSA desenvolveram hiperuricemia leve (ácido úrico 4.36 vs 2.49 mg/dl, CSA vs VEH, p<0.05), com hialinose arteriolar, atrofia tubular, fibrose intersticial em faixa, aumento de proliferação celular e redução da expressão de VEGF. O tratamento com alopurinol ou benzbromarona reduziu a lesão renal, assim como os níveis de ácido úrico e creatinina sérica (ácido úrico 2.03 CSA/ALP e 2.93 mg/dl, CSA/BENZ, p<0.05 vs VEH e CSA). Ambos os tratamentos reduziram a fibrose intersticial, a proliferação celular, infiltrado de macrófagos, expressão de osteopontina e hialinose arteriolar, em associação com restauro da expressão de VEGF, com proteção comparável entre as duas drogas. Conclusão: A hiperuricemia exacerba a nefropatia pela CsA em ratos. Tratamento concomitante com alopurinol ou benzbromarone reduz a severidade da lesão. Como ambas as drogas promovem proteção semelhante, concluímos que o efeito protetor é associado ao controle da hiperuricemia, mais importante que o efeito antioxidante do alopurinol / Abstract: Aim: Hyperuricemia frequently complicates cyclosporine (CSA) therapy. Previous studies have shown that hyperuricemia increases the interstitial and vascular lesions in the cyclosporine model. We therefore tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity. Material and Methods: CSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CSA group). The effect of preventing hyperuricemia on CSA nephropathy was determined by concomitant treatment with the xanthine oxidase inhibitor, allopurinol (CSA-ALP), or with the uricosuric, benzbromarone (CSA-BENZ), in the drinking water. Control groups included rats treated with vehicle (VEH). Histological and functional studies were determined at sacrifice. Results:. CSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with either allopurinol (CSA-ALP) or benzbromarone (CSA-BENZ) reduced renal injury. Both treatments reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis in association with restoration of VEGF expression. Both drugs provided comparable protection. Conclusions: An increase in uric acid exacerbates CSA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. As both drugs promoted similar protection, we can conclude that the protective effect is associated with lowering uric acid levels, more than the antioxidant effect of allopurinol / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

No description available.