Ivabradine improves quality of life in subjects with chronic heart failure compared to treatment with ß-blockers: results of a multicentric observational APULIA study.

OBJECTIVES: Ivabradine (IVA), a selective If current inhibitor decreasing the heart rate (HR) in patients with sinus rhythm, has been added to the most recent European Guidelines on heart failure. This selective treatment reduces HR exclusively while fully preserving myocardial contractility and relaxation, atrioventricular conduction, and ventricular repolarization, as well as blood pressure. The aim of this study was to evaluate the improvement of quality of life (QOL) in patients with chronic heart failure (CHF) treated with IVA versus two ß-blockers (bisoprolol and carvedilol). METHODS: We evaluated if a 1-month treatment with IVA (5 mg b.i.d.) or ß-blockers (carvedilol 6.25 mg b.i.d. or bisoprolol 1.25 mg b.i.d.) improves the QOL (assessed by SF-36 questionnaire) in patients with CHF with reduced left ventricular ejection fraction (<50%). SF-36 was tested in 221 CHF patients (mean age 64 ± 6 years) randomized into two groups (IVA group - 110 patients; ß-blockers group - 111 patients). Data of QOL questionnaire and HR were collected by an interview during a clinical visit both at prescription time (basal) and after 1 month of therapy with IVA or ß-blockers. QOL life and HR results after 1-month of therapy (T1) with IVA were compared with basal values (T0). RESULTS: The IVA versus ß-blockers treatment was associated with a significant improvement of physical functioning (p < 0.001 vs. p < 0.01), physical role functioning (p < 0.001 vs. p < 0.01), emotional role functioning (p < 0.01 vs. p < 0.85), and mental health scales (p < 0.001 vs. p < 0.01). HR in the IVA group was significantly lower compared to the group of patients treated with ß-blockers (63 vs. 67 bpm; p < 0.001). CONCLUSIONS: IVA treatment significantly improves the QOL in patients with CHF without any deleterious impact on hemodynamics, and may be beneficial in these patients without other adverse effects associated with ß-blockers.

Ivabradine improves all aspects of quality of life assessed with the 36-item short form health survey in subjects with chronic ischemic heart disease compared with beta-blockers.

No published studies have evaluated quality of life (QOL) with the 36-item Short Form Health Survey (SF-36) in subjects with chronic stable angina pectoris (CSAP). We evaluated whether a 1-month treatment with 10 mg ivabradine (IVA) or ß-blockers (bisoprolol 2.5 mg/day, carvedilol 12.5 mg/day, atenolol 50 mg/day) improves the QOL in patients with CSAP. The SF-36 was administered to 238 patients randomized in two groups. QOL and heart rate (HR) results after 1 month of therapy with IVA and ß-blockers (T1) were compared with basal values (T0). Treatments in both groups significantly reduced HR (-11 bpm at T1 compared with T0 in the IVA group, -7 bpm at T1 compared with T0 in the ß-blocker group), but IVA demonstrated a more significant (p < 0.001) reduction in HR than ß-blocker treatment (p < 0.01). We observed a significant improvement in all QOL dimensions in the group treated with IVA, in particular in the sections regarding physical functioning, physical role, and general health (p < 0.001). In the group treated with ß-blockers, we found statistically significant improvement only in the physical functioning and physical role sections (p < 0.01). With ß-blocker treatment, many questionnaire sections showed no statistically significant improvement (body pain, social functioning, emotional role, and mental component summary). IVA treatment significantly improves all aspects of QOL in patients with CSAP, unlike ß-blocker treatment. This improvement is associated with a greater reduction in HR.

The effect of intrastriatal injection of liposome-entrapped tyrosinase on the dopamine levels in the rat brain.

Parkinson's disease is a neurodegenerative disorder which is mainly characterized by degeneration of the dopaminergic cells in the nigro-striatal system. Due to a lowered L-tyrosine 3-monooxygenase activity, L-tyrosine is not sufficiently transformed to L-DOPA. To date the most common therapy is the administration of the dopamine precursor L-DOPA, with severe collateral effects. Therefore, the substitution of the lacking tyrosine hydroxylase with tyrosinase might be a novel therapeutical approach that would generate specifically L-DOPA from L-tyrosine. We present here evidence that stereotaxic injection of liposome-entrapped tyrosinase is able to significatively increase the levels of dopamine in the rat brain. The catecholamines L-DOPA, dopamine, L-epinephrine, L-norepinephrine were extracted by acid treatment from the brains and detected by HPLC.

Aging and detoxifying enzymes responses to hypoxic or hyperoxic treatment.

We studied the levels of antioxidant and detoxifying enzymes in the livers and lungs of young and old rats kept under hypoxic or hyperoxic conditions as models of oxidative stress. In particular, we investigated the levels of enzymes directly involved in active oxygen species scavenging (superoxide dismutase, catalase and glutathione peroxidase-selenium dependent) and enzymes challenged with detoxification processes (glutathione transferase, glyoxalase I and glutathione reductase) in order to obtain a wide comparative view of the defence strategies used with respect to the age of the animals. The results show that the responses of some protective enzymes in young rats are opposite to those of old ones. Some of the changes found appear mainly due to age, while others appear to be due only to the oxygen tensions and are independent of the aging process. The glutathione contents of the liver and lung from young and old rats under hypoxic and hyperoxic conditions were measured.

Developmental aspects of detoxifying enzymes in fish (Salmo iridaeus).

The activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione transferase and glyoxalase I have been studied during the embryologic development of rainbow trout (Salmo iridaeus) and in several other trout tissues to investigate the protective development metabolism. A gradual increase of superoxide dismutase, catalase, glutathione reductase, glyoxalase I and glutathione transferase activities was noted throughout embryo development. In all trout tissues investigated glutathione peroxidase was found to be extremely low compared to catalase activity. The highest activity of superoxide dismutase, glyoxalase I and glutathione reductase was found in liver followed by kidney. No change in the number of GST subunits was noted with the transition from the embryonic to the adult stages of life according to the SDS/PAGE and HPLC analyses performed on the GSH-affinity purified fractions.

Cyto-genotoxic species leakage within human melanoma melanosomes. Molecular-morphological correlations.

This work studies the phenotype changes, relating to pigment expression, of a human melanoma cell line. The phenotypic instabilities and proliferation rates are correlated with the production and release in the cell culture medium of active oxygen species and melanin synthesis intermediates. The proliferation rates versus L-tyrosine concentration in the culture media are investigated: a decrease is found when high L-tyrosine is added to the medium. This would be consistent with the release of cytotoxic and/or genotoxic species by melanoma cells. The morphology of melanoma melanosomes is coherent with the leakage of cytotoxic and genotoxic species produced during melanin synthesis.

Specific increase of L-dopa levels in plasma upon infusion of tyrosinase containing liposomes.

1. The present paper reports the effects of liposome-entrapped tyrosinase (EC 1.14.18.1. L-Tyrosine, L-3,4-dihydroxyphenylalanine: oxygen oxidoreductase) infusion on the catecholamine contents of rat plasma. The actions of liposomes and free tyrosinase have also been investigated. 2. From the experiments, evidence has been obtained that liposome-entrapped tyrosinase is able to affect specifically L-3,4-dihydroxyphenylalanine (L-DOPA) levels which increase dramatically. 3. The possible use of liposome-entrapped tyrosinase to raise L-DOPA levels in catecholamine related disorders is discussed. 4. Liposomes without tyrosinase provoke no significant changes of catecholamine or L-DOPA levels while free tyrosinase does induce a change but in a less constant fashion than the liposome-entrapped enzyme.

[Influence of the neurohumoral system on left ventricular performance in chronic congestive heart failure]. / Influenza del sistema neurormonale sulla performance ventricolare sinistra nella insufficienza cardiaca congestizia cronica.

he influence of the neurohumoral system, as adrenergic system or renin-angiotensin system, on cardiac performance in heart failure is not yet know. In order to evaluate the influence of neurohumoral activation in chronic heart failure we followed 51 patients, 47 males and 4 females of mean age 58 +/- 10 years. They suffered from chronic heart failure of different origin and were classified according to NYHA classification: 42 patients were in class III and 9 were in class II. They were treated with digoxin and diuretics since long time. Ejection fraction (EF) was obtained by RVG at baseline and 8 months later. In order to test the influence of adrenergic system on EF we checked plasmatic norepinephrine levels and we divided the patients in two groups: Group A with high levels of plasmatic norepinephrine (1114 +/- 594 pg/ml) and Group B with normal level (426 +/- 139 pg/ml). Group A showed a reduction of EF (-3.73 +/- 1.27%) while, Group B showed a small increase of EF (+ 2.57 +/- 4.32%). To test the influence of renin-angiotensin system we also evaluated the patients according to the value of plasmatic renin activity: normal or high level. We did not observe a significant difference between the 2 groups. Patients with high plasmatic norepinephrine value presented a significant reduction of EF compared to those with low plasmatic norepinephrine. The adrenergic system seems to be more important than renin-angiotensin system or cardiac performance.

[Acute hemodynamic effects of nicardipine in patients with chronic congestive heart failure]. / Effetti emodinamici acuti della nicardipina in pazienti affetti da insufficienza cardiaca congestizia cronica.

We evaluated haemodynamic parameters in 13 patients suffering from chronic heart failure (CHF) in III and IV NYHA class. They were 10 males and 3 females, average age 57 +/- 11 years. Haemodynamic monitoring was made at basal condition and for 40 min after the administration of nicardipine (10 mg iv). We observed that mean arterial pressure and systemic vascular resistances (SVR) showed an important decrease (respectively -10.8%, p less than 0.001 and -22%, p less than 0.001); total pulmonary resistances (TPR) also decreased (-16.6%, p less than 0.001), while mean pulmonary pressure did not show significant reduction. Cardiac index increased with the highest value at the fifteenth minute (-11.7%, p less than 0.01). Pulmonary wedge pressure (PWP) did not show statistic variations, and heart rate too. Cardiac index (CI) did not rise in 3 patients with clinical worsening during the monitoring (patients non responders) (CI increase was less than 15%); while in 10 patients CI increased more than 15% (patients responders). Patients non responders did not show any decrease of TPR and only a transitory reduction of SVR; patients responders showed an important decrease of TPR, SVR, PWP. We observed that at baseline, the difference between the 2 groups was based on the value of TPR and PWP. We conclude that nicardipine is an efficient drug in patients affected by CHF without severe hemodynamic failure.

[Delayed-action nicardipine in the prolonged treatment of chronic congestive heart failure in responsive subjects]. / La nicardipina ritardo nel trattamento protratto della insufficienza cardiaca congestizia cronica in soggetti rispondenti.

We performed hemodynamic monitoring in 13 patients, 10 males and 3 females, mean age 57 +/- 11 years, affected by congestive heart failure, NYHA class III and IV. Hemodynamic evaluation was made at basal condition and for 40 min after the administration of nicardipine (10 mg iv). We observed that in 3 patients cardiac index didn't rise (increase less than 15%) with clinical worsening during the monitoring (patients non responders), while in 10 patients cardiac index increased more than 15% (patients responders). Patients responders, 8 males and 2 females, mean age 57 +/- 10 years, have been treated with oral nicardipine administered at the dosage of 40 mg td for 3 months. Three months after nicardipine treatment we observed a significant increase of exercise capacity and O2 uptake (respectively p less than 0.05 and p less than 0.01); we noted also an improvement of cardio-thoracic ratio and of San Diego index (p less than 0.05). We conclude that patients responders to iv nicardipine receive beneficial clinical effects by chronic oral nicardipine.