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Despite significant improvement of neuroblastoma (NB) patients' survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB's susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.

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UNLABELLED: Organ transplantation is one of the most important achievements of medicine in the 20th century. Ischaemia-reperfusion has a great impact on both: immediate organ function and long-term survival. Organ transplantation can be regarded as a clinical model of ischaemia-reperfusion phenomenon. AIM: The prevention of ischaemia-reperfusion damages. Apoptosis plays a key-role in these processes. METHODS: Apoptosis was investigated in the course of human kidney transplantation. In animal experiments the characteristics of apoptosis were analysed after short ischaemia. Calcium antagonists: verapamil, nifedipine, bepridil, fendiline and (-)-deprenyl, an irreversible selective inhibitor of monoamino oxidase type B, (-)-deprenyl, were administered to prevent apoptosis. RESULTS: The observations showed that in the course of human kidney transplantation necrotic, apoptotic and proliferating renal tubular cells can be observed. All calcium channel blockers and (-)-deprenyl decreased the occurrence and degree of apoptosis in rat kidney. CONCLUSIONS: The functional capacity of tubular cells is a significant factor in the adequate kidney function. The reduction of the apoptosis of tubular cells possibly could improve the function of transplanted kidneys.

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In a 6-week, randomized, double-blind trial, the drug effects of the calcium antagonists, fendiline (75 mg twice daily) and diltiazem (90 mg twice daily), as measured by subjective and objective parameters of coronary heart disease, were studied in 79 patients with stable angina pectoris. The statistical analysis included the data of 71 patients. The results of exercise-ECG tests showed that both medications were effective anti-ischaemic agents. Fendiline was found to be effective in reducing ST-segment depression at maximum comparable load (71 watts) as well as at the time of reaching the individual maximum tolerated load (discontinuation of exertion). Diltiazem, on the other hand, proved effective only at maximum comparable load (72 watts). There was no significant difference between the groups with regard to the reduction after 6 weeks. As regards work tolerance, the duration of exercise and time until appearance of a ST-segment depression of 0.1 mV, before and after treatment comparisons revealed significant changes only in the group receiving diltiazem and the differences between fendiline and diltiazem were statistically significant with regard to these three parameters. Reduction in the frequency of anginal attacks and the diminution of nitroglycerin consumption were comparable in both medication groups, and the changes from baseline were statistically significant. Assessment of the efficacy and tolerability of the medications by patients as well as by investigators revealed no statistically significant differences between the two groups. Blood pressure and heart rate were clearly lowered by diltiazem, whereas fendiline induced only a slight decrease in blood pressure. The results indicate that both medications are equally suited for the treatment of stable angina pectoris.

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Ca2(+)-calmodulin dependent phosphorylation of myosin is essential for the induction of platelet shape change and subsequent reactions. Therefore, we studied the effects of the calmodulin antagonists fendiline and calmidazolium on the thrombin-induced aggregation, secretion of ATP, and increases in the intracellular free calcium concentration ([Ca2+]i) in washed human platelets in the absence and presence of extracellular Ca2+. In Ca2+ free medium, fendiline (10-100 microM) and calmidazolium (3-30 microM) concentration-dependently inhibited aggregation. The effect of fendiline could be partly reversed by extracellular Ca2+ and higher thrombin concentrations. Furthermore, aggregations induced by the calcium ionophore ionomycin and by the protein kinase C-activator 4-beta-phorbol 12-myristate 13-acetate were inhibited by fendiline, although to a smaller degree than the thrombin-induced aggregation. Thrombin-induced secretion of ATP was attenuated by low concentrations of fendiline (1-3 microM) and calmidazolium (1 microM) but enhanced by higher concentrations (10-30 and 3-10 microM, respectively), independently of extracellular Ca2+. Fendiline (1-10 microM) did not affect [Ca2+]i in resting and thrombin-stimulated platelets. At higher concentrations (30-100 microM), it induced increases in [Ca2+]i in unstimulated platelets and attenuated the response to thrombin in Ca2+ free medium, whereas thrombin-induced Ca2+ influx was markedly enhanced. Similar results were obtained with calmidazolium (1-3 microM). These stimulating effects on ATP secretion and on [Ca2+]i of fendiline and calmidazolium may be attributed to interactions with platelet membranes by which the permeability of small cations is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

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The induction of chromosome aberrations (dicentric and ring chromosomes) in human lymphocytes by the antitumor agent bleomycin is synergistically enhanced when bleomycin is applied together with the calcium antagonist fendiline (Sensit).

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One hundred patients with angina pectoris were studied to determine the antianginal effectiveness of senzit, fenigidin and trasicor. The calcium antagonists senzit and fenigidin were found to have high antianginal effect (44% and 78%, respectively) in patients with stable angina pectoris. It was found advisable to use the two drugs in combination with cardiac glycosides in patients with heart failure. A study showed the high antianginal effect of trasicor in postinfarction patients with refractory angina of effort.

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Fendiline was administered intravenously (3 mg) and orally (50 mg and 75 mg) in a cross-over study to six healthy volunteers. The plasma levels of unchanged fendiline and of total radioactivity were measured. Fendiline was absorbed well and its concentration declined biexponentially with mean terminal half-lives of 20-35 h. Since the drug is extensively metabolized, only 12% of total radioactivity in plasma corresponded to fendiline in the case of intravenous administration as compared to less than 2% after oral administration. 56-65% of the administered dose are excreted via the urine and 18-25% with the feces within five days.

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In a randomized cross-over double-blind study of 30 out-patients with true angina the efficacy of fendiline and isosorbide dinitrate (ISDN) was compared. In randomized order the patients daily took either 3 X 50 mg fendiline or 2 X 20 mg ISDN (plus 1 placebo tablet). Each treatment period lasted for six weeks. Ergometric tests were performed at the onset of the study and at intervals of three weeks. The main criterion for the efficacy of the treatment was a change in S-T segment (at 0.06 s after the QRS). With either drug there occurred a statistically significant reduction in S-T depression and in the frequency of anginal attacks during the first treatment period. But there was a difference between the two drugs: Whereas with ISDN a marked reduction in S-T segment depression was observed after three weeks, this effect slightly receded in the second part of the treatment period, while with fendiline the reduction in S-T depression continued over the entire treatment period. There was no significant difference between the two drugs as to side-effects or tolerance.

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