RESUMEN
The discovery and use of cyclosporine since its inception into clinical use in the late 1970s has played a major role in the advancement of transplant medicine. While it has improved rates of acute rejection and early graft survival, data on long-term survival of renal allografts is less convincing. The finding of acute reversible nephrotoxicity and nephrotoxicity in nonrenal transplants has since led to the widely accepted view that there is a chronic more irreversible component to this agent as well. Since that time, there has been intense interest in finding protocols which seek to minimize and even avoid the use of calcineurin inhibitors altogether. We seek to review cyclosporine in terms of its mechanism of action, pathophysiologic, and histologic features associated with acute and chronic nephrotoxicity and recent studies looking to avoid its toxic side effects.
RESUMEN
The aims of this study were to examine the ability of the antioxidant N-acetylcysteine (NAC) and mesalamine (5-ASA) alone and in combination to affect TNBS-induced colitis in rat. Three days following induction of TNBS colitis rats were randomized to receive daily intracolonic treatment with NAC, 5-ASA, and NAC plus 5-ASA for 5 or 8 days. At the end of the treatment period macroscopic and microscopic colonic injuries were scored. Myeloperoxidase (MPO) activity and cytokine gene expression were measured in colonic tissues. Results indicated that treatment with NAC plus 5-ASA caused a significantly greater reduction in colonic injury than either agent alone. Furthermore, combination therapy inhibited significantly MPO activity and inflammatory cytokine gene expression in the distal colon of TNBS-treated animals. The beneficial effects of NAC plus 5-ASA on reduction of colonic injury and promotion of healing were most evident after 8 days of treatment.
Asunto(s)
Acetilcisteína/farmacología , Antiinflamatorios no Esteroideos/farmacología , Colitis/tratamiento farmacológico , Mesalamina/farmacología , Animales , Antioxidantes/farmacología , Biopsia con Aguja , Colitis/patología , Citocinas/análisis , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Inmunohistoquímica , Mediadores de Inflamación/análisis , Masculino , Peroxidasa/efectos de los fármacos , Peroxidasa/metabolismo , Probabilidad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
Epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) have been shown to inhibit gastric acid secretion through stimulation of the EGF receptor (EGFR). In this study we examined in vivo the effects of inhibition of the EGFR on histamine-stimulated acid secretion in the rat. Submaximal (1.5 mg/kg/hr) histamine-stimulated acid secretion was measured (microEq H(+)/2 hr) during infusion of EGFRtk inhibitors and ranitidine in anesthetized rats. EGFR phosphorylation in gastric mucosal tissue lysates was measured by Western blot analysis. Submaximal histamine-stimulated acid secretion was increased significantly by the EGFR inhibitors tyrphostin (Tyr) A46 and Tyr AG1478. Tyr A46 prevented TGFalpha (10 microg/kg/hr)-mediated inhibition of maximal (5.0 microg/kg/hr) histamine-stimulated acid output. Histamine caused a fourfold increase in EGFR phosphorylation which was inhibited by both Tyr and ranitidine. We conclude that the EGFRtk inhibitors, Tyr A46 and Tyr AG1478, significantly increased submaximal histamine-stimulated acid output and Tyr A46 prevented TGFalpha inhibition of histamine-stimulated acid secretion. These observations suggest that the EGFR is involved, in vivo, in the regulation of gastric acid secretion.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/fisiología , Ácido Gástrico/metabolismo , Tirfostinos/farmacología , Animales , Histamina , Antagonistas de los Receptores H2 de la Histamina/farmacología , Masculino , Fosforilación/efectos de los fármacos , Quinazolinas , Ranitidina/farmacología , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador alfa/fisiologíaRESUMEN
BACKGROUND/AIMS: The mechanisms of somatostatin-mediated gastroprotection are not fully understood. Aims of this study were to determine in the rat the role of nitric oxide (NO) in somatostatin-induced effects on gastric mucosal protection and blood flow (GMBF) in the absence and in the presence of intraluminal ethanol. METHODS: Ethanol (70% v/v)-induced gastric mucosal injury after orogastric dosing was quantitated at 30 min and GMBF determined in an ex vivo gastric chamber preparation. RESULTS: Somatostatin (4 microg/kg; i.p.) protection against ethanol-induced ulceration was prevented by the NO inhibitor L-NNA and restored by L-arginine, but not D-arginine. Somatostatin (1-8 microg/kg; i.p.) did not effect basal GMBF. The gastroprotective dose of somatostatin (4 microg/kg; i.p.) prevented the decrease in GMBF caused by ethanol. L-NNA reversed this vascular effect of somatostatin. CONCLUSION: Somatostatin-induced gastroprotection and restoration of GMBF during ethanol exposure involve mechanisms which are dependent on NO generation.