Simultaneous Estimation of Sacubitril and Valsartan Combination of Drug in Tablet Dosage Form Using Hydrotropy by UV Spectrophotometry

Sacubitril/valsartan, traded under the brand name Entresto between others, is a fixed-dose combination medication for use heart failure. Sacubitril is a neprilysin inhibitor (A prodrug) and is used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure. It is anti - hypertensive drug. Valsartan is an Angiotensin Receptor Blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Two UV-spectrophotometric methods have been developed and validated for simultaneous estimation of Sacubitril and Valsartan in a tablet dosage form. The first method employed solving of simultaneous equations based on the measurement of absorbance at two wavelengths, 226.0 nm and 254.0 nm, 𝜆max for Sacubitril and Valsartan, respectively. The second method was absorbance ratio method, which involves formation of Q-absorbance equation at 240 nm (isoabsorptive point) and also at 254 nm (𝜆max of Valsartan). The methods were found to be linear between the range of 4-12 𝜇g/mL for Sacubitril and 2-10 𝜇g/mL for Valsartan using Methanol as solvent. The mean percentage recovery was found to be 96.68%and 101.89% for the simultaneous equation method and 100.2% and 104.53% for the absorbance ratio method, for sacubitril and valsartan respectively. It could be concluded from the results obtained in the present investigation that the two methods for simultaneous estimation of sacubitril and valsartan in tablet dosage form are simple, rapid, accurate, precise and economical and can be used, successfully, in the quality control of pharmaceutical formulations and other routine laboratory analysis. The reviewed highlights various analytical techniques such as high-performance liquid chromatography (HPLC), ultra- performance liquid chromatography (UPLC), UV Spectroscopy, high per-formance thin layer chromatography (HPTLC), liquid chromatography coupled to tandem mass spectrometry (LC- MS), RP-HPLC and other chromatographic method used. The combination of these drugs with different method was examine and the commonly use of the drugs in hypertensive.

The Efficacy and Safety of Sacubitril/Valsartan in Heart Failure Patients: A Review

Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.

Sacubitril/ Valsartan in Advanced Heart Failure: Is it Just a Matter of Contractility or are there Effects on the Pulmonary Circulation? A Real Life Monocentric Experience

Background: Sacubitril/valsartan (S/V), an angiotensin receptor neprilysin inhibitor (ARNI), is the first drug to demonstrate a mortality benefit in patients with chronic heart failure and reduced ejection fraction. S/v had a 20% reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization, compared with subjects receiving enalapril. However, the mechanisms are not clear. The aim of this prospective, non-randomized study was to assess the clinical and instrumental effects of this agent in patients with HFrEF and pulmonary hypertension. Methods: To investigate the effects of S/V in HFrEF, we selected 40 consecutive patients (31 males, 9 females, mean age 64±19 years) in the NYHA class II-III, because they had left ventricular ejection fraction ≤35% at echocardiography. Etiology: 22 CHD, 3 Myocarditis, 15 IDCM. Results: 2 patients took the maximum dose of 97/103 mg, 2 stopped the therapy due to a creatinine increase, all the others took the dose of 49/52 mg. During a mean ± SD follow-up of 24±6 months, no patients died. PASP decreased from 42.71 to 36 mm/Hg (p <0.0001); 6MWT improved from 402 m to 453 m (p <0.0001). Mean LVEF increased from 28.9% to 31.5% p <0.005); NYHA mean class improved from 1.95 to 1.70. An AICD was implanted in 20 patients. Conclusion: These preliminary data suggest that in patients with severe heart failure, S/V is able to improve 6MWT and PASP, even in the absence of a significant improvement of ventricular contractility. S/v may reduce the fluid retention and pulmonary vasoconstriction that contribute to heart failure symptoms.

54 Sacubitril–valsartan (LCZ 696) improves longitudinal strain and ejection fraction in preclinical models treated with doxorubicin through NLRP3, MyD88, and pro-fibrotic chemokines

Aims Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril–valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function and cardiac inflammation in preclinical models. Methods Human Foetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (200 nM) alone or in combination with LCZ-696 (100 mM) for 72 h. After the incubation period, we performed the following tests: cell viability, apoptosis and necrosis; expression of malondialdehyde and 4-hydroxynonenal and concentration of intracellular Ca2+. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; NF-κB). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin i.p. at 2.17 mg/kg (DOXO, n = 6), LCZ-696 at 60 mg/kg (LCZ, n = 6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n = 6). Ejection fraction, radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. Results LCZ-696 exerts cardioprotective effects, enhancing cell viability of 48–54.6% compared to only doxorubicin-treated cells (P &lt; 0.001 for all); LCZ 696 decreased NLRP3, MyD88 and NF-kB expression in cardiac cells. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88 and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (P &lt; 0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Conclusions LCZ-696 exerts direct beneficial effects in cardiomyocytes exposed to doxorubicin. In preclinical models, LCZ-696 reduced inflammation and cytokine expression involved in doxorubicin-mediated cardiotoxicity.