Spotlight on valsartan-sacubitril fixed-dose combination for heart failure: the evidence to date.

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin-angiotensin-aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease.

Alzheimer's disease (AD) is characterized by amyloid beta (A beta) accumulation in the brain and is classified as familial early-onset (FAD) or sporadic late-onset (SAD). Evidences suggest that deficits in the brain expression of insulin degrading enzyme (IDE) and neprilysin (NEP), both proteases involved in amyloid degradation, may promote A beta deposition in SAD. We studied by immunohistochemistry IDE and NEP cortical expression in SAD and FAD samples carrying the E280A presenilin-1 missense mutation. We showed that IDE, a soluble peptidase, is linked with aggregated A beta 40 isoform while NEP, a membrane-bound protease, negatively correlates with amyloid angiopathy and its expression in the senile plaques is independent of aggregated amyloid and restricted to SAD cases. NEP, but not IDE, is over-expressed in dystrophic neurites, both proteases are immunoreactive in activated astrocytes but not in microglia and IDE was the only one detected in astrocytes of white matter from FAD cases. Collectively, our results support the notion that gross conformational changes involved in the modification from "natively folded-active" to "aggregated-inactive" IDE and NEP may be a relevant pathogenic mechanism in SAD.

Neutral endopeptidase expression in mesangial cells.

In the kidney, neutral endopeptidase (NEP) is implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as the atrial natriuretic peptide, bradykinin and angiotensin I. Due to its physiological importance in the modulation of pressor responses, the presence of NEP in mouse mesangial cells has been investigated, since these cells control glomerular function and are able to synthesise components of the renin-angiotensin system. A NEP-like activity (NEP-like) that cleaves the fluorogenic substrates Abz-BKQ-EDDnp and Abz-DRRL-EDDnp was purified from mesangial cell lysate by ion-exchange, followed by gel filtration chromatography. The enzyme was able to hydrolyse bradykinin at the G4-F5 peptide bond and was inhibited by thiorphan. A pH study established that enzyme activity was maximal at pH 7.5 and the determined K(m) was 4.86 M using Abz-DRRL-EDDnp as substrate. NEP-like was recognised by monoclonal anti-NEP and had a molecular mass of 95 kDa. The purified enzyme was sequenced and showed similarity with human, rat, mouse and rabbit NEPs. We isolated, for the first time, NEP-like from mesangial cells. This enzyme could have an important role in the renal physiology by its action upon different peptides that are able to alter renal haemodynamics.

CD10 and CD19 fluorescence intensity of B-cell precursors in normal and leukemic bone marrow. Clinical characterization of CD10(+strong) and CD10(+weak) common acute lymphoblastic leukemia.

In order to assess the age-related changes in CD10 and CD19 fluorescence intensity (FI) the present study analyzed by flow cytometry 56 sternal biopsies from 'normal' infants, children and adults undergoing cardiac surgery. The CD10(+weak) subset was predominant in all age groups, representing approximately 50% of the bone marrow (BM) lymphoid cells in children younger than 4 years. Both CD10+ subsets significantly decreased with age but their ratio did not differ significantly. Moreover, the intensity of CD10 and CD19 fluorescence in the strong and weak subsets did not vary with age. The CD19 intensity was significantly higher in CD10(+weak) than in CD10(+strong) cells. In addition, we classified as CD10(+weak) or CD10(+strong) the leukemic cells from BM aspirates of 117 patients with common acute lymphoblastic leukemia (cALL) (78 children and 39 adults). A higher frequency of cases expressing the CD19+ CD10(+strong) phenotype was observed both in children and adults. Children of the CD10(+weak) group tended to be older than those of the CD10(+strong) group (median = 7 vs. 4 years, P = 0.07), and presented a significantly higher frequency of splenomegaly (93.7 vs. 55%, P = 0.04), which was massive in about 60% of these cases. Among adults, a significantly higher frequency of cases expressing the CD10(+weak) phenotype was observed in females. No other clinical or biological difference was detected between the two groups either for children or adults. Concerning the treatment outcome, we did not observe significant differences in complete remission rate (CRR) or in disease free survival (DFS) among the 32 children and 28 adults analyzed. Finally, we compared the CD10 and CD19 intensity in normal and leukemic BM. Overexpression of either or both antigens in leukemic cells was observed in 42.4% of the cALL cases. In these cases, using cut off values of 110 afu for the CD10 FI and of 100 afu for the CD19 FI, the detection of leukemic cells was possible at levels of 0.2% based on CD10 analysis, of 0.6% based on CD19, and 0.02% when both antigens were overexpressed. In conclusion, we demonstrated that the heterogeneity of CD10 and CD19 fluorescence intensity is of no clinical relevance in cALL, although its study may be helpful for the diagnosis and the detection of minimal residual disease.