For bladder cancer, intravesical chemo/immunotherapy is widely used as adjuvant therapy after surgical transurethral resection. Bacillus Calmette-Guerin (BCG) is a live attenuated Mycobacterium of the same family as tuberculosis, that is capable of inducing a local inflammatory response upon instillation into the bladder. Intravesical therapy with BCG has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors than most chemotherapeutic agents used for the same indication. However, compared to intravesical chemotherapy, BCG immunotherapy provokes more pronounced local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. Nanoparticles with positive surface charge and mucoadhesive properties were developed to overcome these side effects. Hence, the aim of this study was to optimize and evaluate cationic chitosan (CS) nanoparticles encapsulating BCG in terms of antitumor efficacy after intravesical administration in bladder tumor, induced in rat model. It was found that nanoparticle formulations of 269-375 nm in size can be produced with 42% encapsulation efficiency. The zeta potential was positive and was suitable for intravesical administration. Antitumor efficacy was determined over the parameters of histopathological evaluation, survival rate and mean bladder weight in comparison to treatment with commercial BCG solution. Concerning survival rates, BCG-loaded chitosan nanoparticles resulted in significantly longer survival than BCG commercial product (up to 86 days of survival with no systemic side effects). When compared to healthy bladder weight averages, all groups (especially BCG commercial solution) showed higher bladder weights confirming tumor formation. Histopathological findings confirmed antitumor activity in all treatment groups and optimum findings were observed in groups treated with CS nanoparticles encapsulating BCG. At the same time, significant nanoparticle accumulation in bladder tissues was observed especially for BCG-loaded CS group. In this study, it was clearly observed that cationic CS nanoparticles provide a significantly improved perspective in intravesical immunotherapy of bladder tumors.

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We investigated the role of adenosine receptors in amitriptyline-induced cardiac action potential (AP) changes in isolated rat atria. In the first group, APs were recorded after cumulative addition of amitriptyline (1 μM, 10 μM and 50 μM). In other groups, each atrium was incubated with selective adenosine A(1) antagonist (8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 10(-4) M) or selective adenosine A(2a) receptor antagonist (8-(3-chlorostyryl) caffeine, 10(-5) M) before amitriptyline administration. Resting membrane potential, AP amplitude (APA), AP duration at 50% and 80% of repolarization (APD(50) and APD(80), respectively), and the maximum rise and decay slopes of AP were recorded. Amitriptyline (50 μM) prolonged the APD(50) and APD(80) (p < 0.001) and the maximum rise slope of AP was reduced by amitriptyline (p < 0.0001). Amitriptyline reduced maximum decay slope of AP only at 50 μM (p < 0.01). DPCPX significantly decreased the 50-μM amitriptyline-induced APD(50) and APD(80) prolongation (p < 0.001). DPCPX significantly prevented the effects of amitriptyline (1 μM and 50 μM) on maximum rise slope of AP (p < 0.05). DPCPX significantly prevented the amitriptyline-induced (50 μM) reduction in maximum decay slope of AP (p < 0.001). The selective adenosine A(1) receptor antagonist prevented the electrophysiological effects of amitriptyline on atrial AP. A(1) receptor stimulation may be responsible for the cardiovascular toxic effects produced by amitriptyline.

We aimed to investigate the possible roles of nitric oxide (NO) and endothelin on the changes of cardiac muscle function in both hyper- and hypodynamic septic shock periods. Cecal ligation and puncture was performed in 50 Wistar albino rats to induce septic shock. Changes in atrium and right ventricle papillary muscle contractions, atrium beat rate, adrenergic and cholinergic responses in these tissues were evaluated in vitro. Atrium beat rate increased in hypodynamic period ( p < 0.001) that was reversed by bosentan ( p < 0.001) and NG-nitro-l-arginine methylester (l-NAME; p < 0.05). Atrium contractions decreased in both hyper- and hypodynamic periods ( p < 0.001) that were partially ameliorated by bosentan in both periods ( p < 0.01) and only in hypodynamic period by l-NAME ( p < 0.001). l-NAME increased papillary muscle contractions in both periods ( p < 0.01), but bosentan increased it only in hyperdynamic period ( p < 0.01). Bosentan and l-NAME increased potency of isoproterenol on atrium beat rate in both periods and increased carbachol potency on atrium beat rate and atrium contraction amplitude only in hypodynamic period. Bosentan increased atrium contraction response to isoproterenol in hypodynamic period ( p < 0.05). Papillary muscle contraction response to isoproterenol increased in hypodynamic period ( p < 0.05). l-NAME increased papillary muscle contraction response to carbachol in both periods ( p < 0.01, p < 0.05, respectively). These results show that NO and endothelin may play a role in positive inotropic and negative chronotropic effects for atrium in septic shock. Bosentan and l-NAME may change potency and efficacy of isoproterenol and carbachol via upregulation of adrenergic and cholinergic receptors and/or through post receptor factors.