Daglutril

Peptides, such as CNP, CGRP and VIP, are involved in the function of male penile erectile tissue. Tissue levels of said peptides are controlled by the endopeptidase enzymes. Theoretically, the inhibition of the degradation of CNP, CGRP and/or VIP should result in an enhancement in penile smooth muscle relaxation. The effects were investigated of CNP or VIP (0.1 nm-1 μm), without and following pre-exposure of the tissue to a threshold concentration of the endopeptidase inhibitor KC 12615 (10 μm, for 20 min), on the reversion of tension induced by means of electrical field stimulation. Drug effects on the production of cyclic AMP/GMP were also evaluated. Neither KC 12615, CNP and VIP nor the combination of CNP plus KC 12615 or VIP plus KC 12615 increased the response of the tissue to EFS. While no effects were observed of a pre-exposure of the tissue to KC 12615 on the production of cyclic AMP in the presence of VIP, an enhancement was registered in the accumulation of cyclic AMP in the presence of CNP plus KC 12615. Further studies are indicated to investigate whether endopeptidase inhibitors might tend to be more effective in tissues affected by a decreased local production of vasoactive peptides.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Blockade of this system is commonly used in the treatment of cardiovascular (CV) and renal disease.

Data from multiple clinical trials have provided good evidence about the benefit of blocking the system as a therapeutic target to reduce CV and renal events. We have reviewed all the tested combinations of different drugs counteracting the effects of the renin-angiotensin-aldosterone system.

Monotherapy with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) remains valid in all the guidelines, whereas their dual combination has been discarded due to the absence of proven benefits in high CV risk patients and in patients with chronic kidney disease (CKD). The combination of the standard therapy with an ACEi or an ARB with a mineralocorticoid receptor blocker is a valid option, but has the inconvenience of frequent hyperkalemia in patients with CKD. Similarly, the addition of the direct renin inhibitor, aliskiren, to this standard therapy is not particularly supported in diabetic patients. New dual-acting blockers, for example, those combining valsartan and neprilysin inhibitors (LCZ696-Novartis) or endothelin converting enzyme inhibitors and neprilysin inhibitors (ECEI, Daglutril-Solvay), are currently under investigation.