Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines.

Hepatocyte growth factor (HGF)-stimulated Met signaling influences tumor survival, growth and progression, all processes involving the transcription factor NF-kappaB. NF-kappaB plays a complex role in the control of survival due to the influence of cellular factors acting downstream. We undertook a comparative investigation of two human breast carcinoma cells with different grades of malignancy and HepG2 hepatoma cells, which present a biphasic response to HGF (proliferation followed by apoptosis). We found evidence that HGF induced gene patterns characteristic of survival rather than apoptosis depending on the cell type. The ability of NF-kappaB to regulate expression of hypoxia-inducible factor-1alpha (HIF-1alpha), a survival/anti-apoptotic gene in cancer, seemed to be critical. In the HepG2 and MCF-7 (low invasive breast carcinoma) cell lines increased transcription and translation were responsible for HIF-1alpha induction after HGF. The regulation by NF-kappaB was mainly at the level of the 5'-UTR of the HIF-1alpha message. HIF-1 (alpha/beta heterodimer) was likely to transactivate Mcl-1, another anti-apoptotic gene. Opposite results were observed in MDA-MB-231 cells (highly invasive breast carcinoma), which have high NF-kappaB activity, further inducible by HGF, because HIF-1alpha mRNA expression and HIF-1 transactivating capacity were HGF-insensitive while the alpha subunit seemed to be degraded after HGF. However, ornithine decarboxylase (ODC) and heme oxygenase mRNA expression persistently increased. By transiently transfecting two ODC gene reporters we demonstrated that ODC is a target gene of NF-kappaB in HGF-treated tumor cells. By regulating HIF-1 activity and specific gene expression downstream, NF-kappaB may influence the survival threshold, with an impact on the fate of carcinoma cells after prolonged HGF treatment.

[Comparison of amiodarone and quinidine in the conversion to sinusal rhythm of atrial fibrillation of recent onset]. / Confronto tra amiodarone e chinidina nella conversione a ritmo sinusale della fibrillazione atriale di recente insorgenza.

The effectiveness of amiodarone and quinidine in converting atrial fibrillation of recent onset (less than three weeks) to sinus rhythm was compared in a randomized, open-label study. Patients with signs of heart failure determining a NYHA class 3 or 4, acute myocardial infarction, unstable angina pectoris, sick sinus syndrome, Wolff-Parkinson-White syndrome, conduction disturbances, dysthyroidism, or undergoing concomitant therapy with antiarrhythmic drugs, were excluded from the study. Sixty-eight consecutive patients were randomized to receive amiodarone (group A) or quinidine (group B). Group A was treated with amiodarone intravenously as a bolus of 5 mg/Kg over a 20 min period followed by a 15 mg/Kg infusion during the first 24 hours and then orally at a dose of 0.4 g every 6 hours. Group B was treated with quinidine sulphate orally at a dose of 0.2 g every 6 hours during the first day; 0.4 g every 6 hours the second day and 0.6 g every 6 hours during the third day of therapy. Quinidine was preceded by rapid intravenous digitalization depending on the patient's clinical status so as to obtain a ventricular rate of about 100 beats/min, with subsequent oral digitalis administration in maintenance doses. Both treatments were continued until conversion or for a maximum of three days. If the sinus rhythm was not restored, patients underwent electrical cardioversion. Drug efficacy was assessed on the basis of conversion to sinus rhythm. Six patients converted to sinus rhythm with intravenous digitalization alone and were excluded from the comparison between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic effects of transdermal nitroglycerin in stable angina pectoris: a within-patient, placebo-controlled study.

The efficacy of transdermal nitroglycerin patches, releasing 20 mg of active substance over a period of 24 h (TDN 20), was investigated in 10 patients with stable exercise-induced angina pectoris. The study was divided into 3 periods: the first part was an acute, within-patient, crossover, double-blind, placebo-controlled study, in which patients performed a cycloergometric exercise test 4 and 24 h after the application of the patches (TDN 20 or placebo). During the 2nd period, patients were given TDN 20, in single blind conditions, for 4 weeks and another exercise test was performed, on the last day, 4 and 24 h after patch application. Finally, after a one-day placebo wash-out, a second acute study similar to the first was performed. Four h after dosing, exercise duration to 1 mm ST segment depression was 441 s and 314 s (p less than 0.01) for TDN 20 and placebo, respectively (first acute study), 394 s for TDN 20 after chronic treatment (p less than 0.001 vs acute placebo) and 472 and 354 s (p less than 0.001) for TDN 20 and placebo, respectively (second acute study). No difference in exercise duration to 1 mm ST segment depression was found between TDN 20 and placebo, 24 h after administration, in any of the periods. Blood pressure significantly decreased and heart rate significantly increased 4 h after TDN dosing (in comparison with placebo) in both the acute studies, but no difference was observed after chronic TDN treatment. In conclusion, TDN 20 increases exercise tolerance 4 h after the application of both acute and chronic treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prognostic meaning of the echo-dipyridamole test in recent non-Q myocardial infarct]. / Significato prognostico del test eco-dipiridamolo nell'infarto miocardico non Q recente.

The aim of this study was to evaluate the usefulness of the dipyridamole-echocardiography test soon after non Q wave myocardial infarction. Forty-two consecutive patients admitted to the Coronary Care Unit for a first episode of a non Q wave myocardial infarction were enrolled. Dipyridamole-echocardiography test and exercise stress test were performed on 29/42 patients without clinical or electrocardiographic evidence of residual ischaemia, before hospital discharge (from 7 to 15 days after admission). They were followed-up for 1 to 15 months (mean 11.9) or until one of the following clinical end points occurred: recurrence of myocardial infarction, angina or cardiac death. Over a period of 4 minutes, 0.56 mg/kg of dipyridamole was infused intravenously. The test was considered positive when a new transient wall motion abnormality was confirmed by two independent observers. According to these criteria a positive test was observed in 7/29 patients (24%) and a negative one in 22/29 (76%). The exercise stress test was positive in 12/27 patients (44%). Subsequent coronary events occurred in all the patients (100%) with positive dipyridamole-echocardiography test and in 7/22 patients (32%) with negative dipyridamole-echocardiography test (p less than 0.001). Five out of the 7 patients with positive test who underwent coronary angiography showed multivessel coronary artery disease. The sensitivity, specificity and positive predictive value of dipyridamole-echocardiography test for the identification of patients at risk for subsequent coronary events were respectively 50%, 100%, 100%, while for exercise stress test these values were 83%, 86% and 75%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a transdermal patch system containing nitroglycerin on exercise tolerance in patients with angina pectoris. Double-blind, placebo controlled, comparison with slow-release nifedipine and verapamil.

The antianginal efficacy of nitroglycerin (NTG), given in a new transdermal therapeutic system (TTS), was compared with that of nifedipine and verapamil, both in slow-release (SR) formulation, in a randomized, double-blind, placebo-controlled study, carried out in 8 patients with stable exercise-induced angina pectoris. TTS NTG 40 cm2 (releasing 20 mg of NTG over 24 hours), nifedipine 20 mg SR, verapamil 120 mg SR and placebo were given once on 4 consecutive days according to a 4 X 4 latin-square design, twice replicated. A cycloergometric symptom-limited exercise test was performed 4 and 8 hours after the administration of each drug. Four hours post-dosing, mean exercise duration was 407 sec. after placebo and 523 (+28%) and 485 (+ 19%) sec. after TTS NTG and nifedipine SR respectively, while at the 8th hour it was 375 sec. after placebo, and 515 (+ 37%) and 457 (+ 21%) sec. after TTS NTG and nifedipine SR. Exercise duration after verapamil was similar to that after placebo. In comparison with placebo maximal workload and total work performed were significantly higher on TTS NTG and on nifedipine at both times of observation, but no significant differences were seen after verapamil. Peak exercise systolic blood pressure was nearly identical after all the treatments tested. Peak exercise heart rate and pressure rate product were both significantly higher on TTS NTG, as well as on nifedipine, in comparison with placebo, while values after verapamil did not differ from those after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

[Drug therapy combinations in angina pectoris]. / Associations médicamenteuses dans l'angine de poitrine.

The critical level of myocardial oxygen consumption at which anginal pain will occur can be assessed in patients with coronary artery disease. We studied the results of exercise ECG in patients with effort angina, administered placebo, nitrate derivatives, betablockers, and calcium inhibitors, alone and in different associations. Nitrate derivatives and calcium inhibitors appeared to be more effective than betablockers. The study demonstrated the utility of the association of betablockers with other drugs with a more effective anti-anginal action but without the hypotensive or antiarrhythmic effects of betablockers which are often very desirable in the treatment of coronary artery disease.

[Verapamil in effort angina: a multi-centre study]. / Il verapamil nell'angina da sforzo: valutazione policentrica.

We have performed a multi-centre study with 47 outpatients in order to evaluate the efficacy of Verapamil (V) in the treatment of stable effort angina, and to compare the effect of two different doses of the drug (240 and 360 mg/die). The protocol consisted of a first period of Placebo, followed by the double-blind randomized cross-over administration of Placebo (P) and Verapamil (V) in doses of 240 and 360 mg/die. The symptomatology, the consumption of TNG, the ECG pattern at rest and during exercise, the maximum exercise tolerance during exercise and the rate of recovery were evaluated at the end of each 1 month period. V. provided a significant reduction of the number of angina attacks and of the consumption of TNG pills with improvement of symptomatology. The maximum exercise performance improved without changes in maximum rate pressure double product. A decrease of double product was observed at rest and during the recovery period. The higher dose of V. (360 mg/die) provides a better improvement in the number of angina attacks, in the symptomatology, in the double product at rest, and in the rate of recovery than the lower dose (240 mg/die). Thus these data indicate that V. provides anti-anginal efficacy by reducing myocardial oxygen demand, and increases exercise tolerance in effort angina patients.

Effects of nifedipine, acebutolol, and their association on exercise tolerance in patients with effort angina.

The action of nifedipine (N), acebutolol (A), and their association (A+N) was studied in 16 patients suffering from effort angina with documented coronary artery disease. The therapeutic action was valued by bicycle effort stress test after oral administration of medications in comparison with placebo (P), following a double-blind random sequence of treatments. Working capacity significantly increased after A (507 +/- 450 mkp, p less than 0.05), after N (1,140 +/- 767 mkp, p less than 0.001), and after A+N (1,198 +/- 644 mkp, p less than 0.01). The increments of work after P administration were not significant. Moreover, fatigue instead of angina appeared as a stopping criterion in 8 patients after A+N, and in only 1 patient after P, A, and N.

Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exercise-induced angina pectoris.

According to the experimental model of a 5 X 5 Latin square, 5 treatments were studied single blind in 5 patients, affected by stable-effort angina, by means of exercise tests. In the period of maximal supposed effect the following treatments were investigated: placebo (P), 1 tablet, orally; isosorbide dinitrate (ISDN), 5 mg, sublingually; propranolol (Pr), 40 mg, orally; nifedipine (N), 10 mg, orally; verapamil (V), 160 mg, orally. Placebo, compared with its own control tests, did not change any of the examined parameters. Comparison of the 'active' treatments with P showed the following results. All the treatments increased the duration of work before ECG positivity appearances. An increase in duration of work and total work performed before angina was seen after administration of ISIDN, N and V; the improvement observed after treatment with Pr was not significant. Comparison of treatments showed that work performance before angina was the same after administration of ISDN, N and V; these treatments were more effective than that with 40 mg Pr. Duration of work before ECG positivity was significantly longer after ISDN and N than after Pr. The changes in heart rate, maximal arterial pressure, ejection time index and triple product confirmed the activity of the administered doses. According to the observed effects on exercise tolerance, in comparison with P the same level of work was performed with the same triple product after Pr, and with lower triple products after ISDN, N and V.

[Effects of the association of Ca-antagonists with nitroderivatives or betablocking drugs in effort angina pectoris (author's transl)]. / Associazione dei farmaci calcio-inibenti con nitroderivato e beta-bloccante nell'angina pectoris da sforzo.

The effects of the association of calcium antagonists (CAI) with a nitroderivate and a betablocker were studied by means of exercise tests in 8 patients with stable effort angina pectoris. According the statistical model of a latin square 4 x 4, the first 4 patients were tested with the following treatments: placebo, oral; nifedipine (N) 10 mg, oral; N + isosorbide dinitrate (ISDN) 10 mg oral; N + propranolol (Pr) 40 mg, oral. In the second square verapamil 80 mg oral represented the CAI treatment. Compared to placebo, all the treatments produced a significant increase of exercise duration and total work performed before angina. In both the squares the improvement observed after CAI + ISDN was significantly higher than after administration of CAI alone. In both the squares the association of CAI + Pr determined a little, non significant improvement of exercise duration in respect to CAI alone. EKG positivity was delayed by Pr more than angina appearance: hpwever, also this effect was not significant when compared with administration of CAI alone. By the analysis of the changes of heart rate, maximal arterial pressure, ejection time and triple product at the same level of work, a relevant inhibition of myocardial contractility with the adopted doses of CAI can be excluded; the effect of these drugs seems to be due mainly to a decrease of arterial pressure, and, when associated to ISDN, to decreases of arterial pressure and ejection time.

[Effectiveness of nifedipine on exercise tolerance in patients with angina pectoris. Comparison with a nitroderivative and a beta-blocking agent]. / Efficacia della nifedipina sulla tolleranza allo sforzo di pazienti anginosi. Confronto con nitroderivato e betabloccante.

The effect of nifedipine on effort angina was investigated by means of exercise tests with bycicle ergometer and compared, in the same patients, with the effects of a nitroderivative and a betablocking agent. Five patients with stable effort angina entered the study, after an hemodynamic and contrasto-graphic control. According to the protocol of a latin square 5 X 5, all the patients received in a random sequence the following treatments: placebo, 1 c. orally; isosorbide dinitrate, 5 mg sublingually; propranolol, 40 mg orally; nifedipine, 10 mg sublingually; nifedipine, 10 mg orally. No significant change of any of the considered parameters was observed after the placebo. Isosorbide dinitrate and nifedipine produced significant increases of the duration of work before appearance of pain and EKG positivity, and of total work performed before anginal pain. Only the duration of work before EKG positivity was improved by propranolol. The comparisons between treatments showed no significant difference of the effects of the administered doses of isosorbide dinitrate and nifedipine. The improvements observed after propranolol were significantly lower than that observed after isosorbide dinitrate and oral nifedipine. On the basis of the observed changes of cardiac rate, maximal arterial pressure, ejection time index and triple product, the authors evaluate the possible mechanism of action of nifedipine.

[Use of atrial pacing in diagnosis of coronary insufficiency. Comparison between coronarography and exercise test (author's transl)]. / Impiego dell'atrial pacing nella diagnosi di insufficienza coronarica. Confronto con la coronarografia e con la prova da sforzo

--123 atrial pacings (AP) performed as diagnostic investigations in patients with chest pains were re-examined. By using floating catheter without fluoroscopic control, this technique is very simple to perform and free from relevant risks. The diagnostic sensibility and specificity of AP were examined in 93 patients in which a coronary arteriography was performed; these figures were compared with the corresponding values observed in 65 patients in which an adequate diagnostic exercise test (ET) was also available. The diagnostic sensibility of AP examined in 63 patients with significant coronary artery disease was 90%; the corresponding value of ET was 79%. In particular, in patients with single vessel disease, the sensibility of AP (90%) was much higher than that observed in ET (40%). The specificity of AP examined in 30 patients free from significant stenosis of the coronary arterial tree was 43%. This value was largely lower than that observed in ET (82%) in the same patients, and appears to be inadequate for validation AP as a diagnostic tool in coronary heart disease. Therefore, AP must be limited to functional, and not diagnostic, evaluation of patients in which the diagnosis of coronary heart disease can be made by other means.

[The effects of verapamil on angina threshold during exercise (author's transl)]. / Effetti della somministrazione acuta di verapamil sulla soglia d'angor da sforzo

The efficacy and duration of the effects of verapamil on angina threshold during exercise were examined in five patients with proved angina pectoris, with the experimental model of a latin square 5 X 5. The effects of verapamil (0,1 mg/kg i.v.) were compared with those of a placebo (20 ml saline i.v.), of isosorbide dinitrate (5 mg, sublingual), of propranolol (0,1 mg/kg i.v.), and of dipyridamol (20 mg i.v.). All the treatments were studied within 20 minutes after administration; the efficacy of the "drugs" was checked against placebo. Verapamil and isosorbide dinitrate significantly prolonged the duration of exercise and total amount of work done before angina and EKG alteration appearance. Similar changes were observed after propranolol, but not significantly different from the effects of placebo. Dipyridamol reduced thw work performance, without significant difference from placebo. The effects of verapamil, though less marked than its peak effects, were still present 70 minutes after administration. The possible mechanism of work performance improvements induced by verapamil in angina pectoris is briefly discussed on the basis of the Triple Product changes observed during exercise.

[Orally administered nitroderivates: efficacy and duration of the effects of isosorbide dinitrate (author's transl)]. / Nitroderivati per via orale. Efficacia e durata di azione del dinitrato di isosorbitolo

The effects of 20 mg of orally administered isosorbide dinitrate on 10 patients with stable angina pectoris were studied by means of exercise tests. First, the reproducibility of the angina threshold of each patient was controlled; then the effects after 60, 150 and 210 minutes after administration of the drug and of a placebo, given in a random sequence, were studied. No significant changes of the parameters examined were observed after the placebo. A significant increase of duration of exercise and total amount of work performed before appearance of angina were observed after the drug. These changes were maximal in tests made 60 minutes after administration of the drug, declining thereafter; nevertheless, statistically significant differences from placebo were also observed in tests performed after 150 and 210 minutes. The appearance of ischemic ST changes was retarded by the administration of the drug. Disappearance of pain after interruption of exercise was significantly quicker when compared with the observations made after placebo.

[Long-term effects of sublingual isosorbide dinitrate (author's transl)]. / Effetti e durata di azione del dinitrato di isosorbitolo per via sublinguale

The effect of 10 mg of sublingual isosorbide dinitrate were studied using exercise test in 10 patients with stable angina pectoris. First the reproducibility of angina threshold of each patient was controlled. then the effects after 30, 90, 150 minutes of the administration of the drug and a placebo, administered in random sequence, were studied. No significant changes of the parameters examined were observed after the placebo. Significant increase of duration of exercise and total amount of work performed before angina were observed after the drugs. Also, the appearance of electrocardiographic alterations was retarded, and disappearance of pain after exercise interruption was quicker. These changes were maximal in the tests made 30 minutes after administration of the drug, declining therafter; nevertheless, statistically significant differences from placebo were also observed in tests after 90 and 150 minutes.