Major adverse cardiovascular events related to phosphodiesterase 5 inhibitors: analysis of real-life data from Eudra-Vigilance database.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the standard medical treatment for erectile dysfunction. Aim of our study was to evaluate the rate of major adverse cardiovascular events (MACE) reported during PDE5i treatment based on Eudra-Vigilance (EV) reports. METHODS: EV database is the system for managing and analyzing data on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area. MACE are defined as non-fatal stroke, non-fatal myocardial infarction, non-fatal congestive heart failure, revascularization after aorto-coronary graft bypass and cardiovascular death. We recorded the number of MACE for sildenafil, tadalafil, vardenafil, avanafil per category and severity until 1st July 2023. Pooled Relative Risk (PRR) was used to compare data between drugs. RESULTS: Overall, 951 MACE events were reported. Most of them were observed in younger patients <65 years old (452/951 events, 48%). Overall, 377/8939 (4%) MACE events were observed for sildenafil, 221/5213 (4%) for tadalafil, 50/1029 (4%) for vardenafil and no events for avanafil. No significative differences were reported comparing sildenafil and tadalafil (PRR 0.71-0.99, IQR 0.61-1.35, P>0.05), neither sildenafil vs. vardenafil (PRR 0.68-0.79, IQR 0.43-1.55, P>0.05), neither tadalafil vs. vardenafil (PRR 0.77-0.95, IQR 0.64-1.30. P>0.05) even when compared for age. Comparison between different classes of age showed MACE were more frequent in patients younger than 65 years old taking sildenafil and tadalafil when compared to patients older than 85 years old (PRR 0.02-0.11. IQR 0.01-0.40. P<0.01) and when compared to patients in 65-85 class of age (PRR 0.02-0.12, IQR 0.01-0.95, P<0.01). CONCLUSIONS: Real life data is consistent with MACE related to PDE5i. PDE5is are infrequently (<5%) associated with MACE. However, risk seems higher in younger patients, particularly for sildenafil (452/951 events, 48%). Clinicians should consider these data when prescribing PDE5i especially in young patients.

Atrial natriuretic peptide predicts disease progression and digital ulcers development in systemic sclerosis patients.

AIMS: Systemic sclerosis (SSc) is an autoimmune disease characterized by micro/macrovascular damage due to the underlying fibrosis. Markers able to predict the progression of cardiovascular damage, including digital ulcers, in SSc are warranted. We aimed at characterizing the relevance of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide plasma levels in relation to cardiovascular damage and digital ulcers in a cohort of Italian SSc patients. METHODS: Seventy patients were enrolled (64 women and six men; mean age 56.7 ±â€Š14 years) with a disease duration of 11.1 ±â€Š8.3 years. Clinical, instrumental (nailfold videocapillaroscopy, ECG, transthoracic echocardiography, pulmonary function test with diffusion lung CO), NT-proANP and N-terminal probrain natriuretic peptide plasma levels measurement were performed at baseline. The clinical follow-up lasted 24 months. The statistical approach used to achieve the study objectives included multivariate analysis, receiver operating characteristic curve, Kaplan-Meier and Cox regression analyses. RESULTS: Both NT-proNPs levels correlated with systolic pulmonary arterial pressure, but only the NT-proANP level correlated with right heart dimension. Both NT-proNPs levels were higher in patients experiencing events at follow-up but only the NT-proANP level significantly predicted the progression of cardiovascular damage, including development of pulmonary arterial hypertension (PAH). NT-proANP levels were higher in patients with digital ulcers and strongly predicted their development. CONCLUSION: Our results show that the NT-proANP plasma level significantly correlates with disease progression such as new onset of PAH, worsening of pulmonary hypertension and development of digital ulcers in a cohort of SSc Italian patients. If future studies will confirm our findings, the plasma NT-proANP level could be used in clinical practice as a novel sensitive marker for PAH and digital ulcers development in SSc.

Effects of cadmium on the glial architecture in lizard brain.

The glial cells are positioned to be the first cells of the brain parenchyma to face molecules crossing the blood-brain barrier with a relevant neuroprotective role from cytotoxic action of heavy metals on the nervous system. Cadmium is a highly toxic metal and its levels in the environment are increasing due to industrial activities. This element can pass the blood-brain barrier and have neurotoxic activity. For this reason we have studied the effects of cadmium on the glial architecture in the lizard Podarcis siculus, a significant bioindicator of chemical exposure due to its persistence in a variety of habitats. The study was performed on two groups of lizards. The first group of P. siculus was exposed to an acute treatment by a single i.p. injection (2 mg/kg-BW) of CdCl2 and sacrificed after 2, 7 and 16 days. The second one was used as control. The histology of the brain was studied by Hematoxylin/Eosin and Cresyl/Violet stains while the glial structures were analyzed by immunodetection of the glial fibrillary acidic protein (GFAP), the most widely accepted marker for astroglial cells. Evident morphological alterations of the brain were observed at 7 and 16 days from the injection, when we revealed also a decrease of the GFAP-immunopositive structures in particular in the rhombencephalic ventricle, telencephalon and optic tectum. These results show that in the lizards an acute exposure to cadmium provokes morphological cellular alterations in the brain but also a decrement of the expression of GFAP marker with possible consequent damage of glial cells functions.

Neurodegeneration in zebrafish embryos and adults after cadmium exposure.

Cadmium is a biologically non-essential metal. It is also toxic to many organs including the brain. The aim of this study was to analyse the neurodegenerative effects of this metal in embryos and adults of zebrafish exposed to sub-lethal concentrations of cadmium. The study was performed by cytochemical stainings. Six hours after fertilisation (hpf) zebrafish embryos were treated for 24 hours with 9 λM of cadmium and subsequently stained with Acridine orange in whole mount to detect apoptosis in the brain. Adult zebrafish were treated for 16 days with the same concentration of cadmium, and cell death in the brain was detected by Fluoro-Jade B staining at 2, 7 and 16 days of treatment. An increase in cell death was observed only at 16 days of treatment in adults, while an increase in apoptotic events was revealed in the brain of embryos after 24 h of treatment. This evidence is indicative that cadmium, even at a sub-lethal concentration, induces cell death in the brain of embryos but also in adults of zebrafish in which the phenomenon appears time-dependent.Â.

Neuroglial alterations in the zebrafish brain exposed to cadmium chloride.

Cadmium is an extremely toxic heavy metal that widely occurs in industrial workplaces with various hazardous effects on brain functions. The cytotoxic effects of cadmium chloride (CdCl2 ) on the neuroglial components of the zebrafish brain were analysed by detecting the glial fibrillary acidic protein (GFAP) expression and the mRNA levels of myelin genes mbp, mpz and plp1 in adult specimens exposed to cadmium for 2, 7 and 16 days. A significant decrease in the GFAP protein by Western blotting experiments was observed after 2 days of treatment, reaching 55% after 16 days. No change was observed in the mRNA levels. Using immunohistochemistry, a reduction in GFAP-positive structures was revealed with a progressive trend in all the brains at 2, 7 and 16 days of treatment. In particular, a considerable reduction in GFAP-positive fibres, with a different course, was observed in the ventricle areas and at the pial surface and in blood vessels after 16 days. Our experiments also showed a structural and chemical alteration of myelin and upregulation of mpz mRNA levels, the oligodendrocyte gene that is upregulated in experiments of neuronal injury, but not of plp1 and mbp mRNA levels, other myelin structural genes. These data confirm the toxic action of cadmium on the zebrafish brain. This action is time-dependent and involves the glial cells, key components of the protection and function of nerve cells, hence the basis for many neurological diseases. Copyright © 2016 John Wiley & Sons, Ltd.