The application of QSAR along with other in silico tools like molecular docking, and molecular dynamics provide a lot of promise for finding new treatments for life-threatening diseases like Type 2 diabetes mellitus (T2DM). The present study is an attempt to develop Monte Carlo algorithm-based QSAR models using freely available CORAL software. The experimental data on the α-amylase inhibition by a series of benzothiazole-linked hydrazone/2,5-disubstituted-1,3,4-oxadiazole hybrids were selected as endpoint for the model generation. Initially, a total of eight QSAR models were built using correlation intensity index (CII) as a criterion of predictive potential. The model developed from split 6 using CII was the most reliable because of the highest numerical value of the determination coefficient of the validation set (r2VAL = 0.8739). The important structural fragments responsible for altering the endpoint were also extracted from the best-built model. With the goal of improved prediction quality and lower prediction errors, the validated models were used to build consensus models. Molecular docking was used to know the binding mode and pose of the selected derivatives. Further, to get insight into their metabolism by living beings, ADME studies were investigated using internet freeware, SwissADME.

Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease. In acute heart failure, and especially in cardiogenic shock related to ischemic conditions, vasopressors and inotropes are used. However, both pathophysiological considerations and available clinical data suggest that these treatments may have disadvantageous effects. The inodilator levosimendan offers potential benefits due to a range of distinct effects including positive inotropy, restoration of ventriculo-arterial coupling, increases in tissue perfusion, and anti-stunning and anti-inflammatory effects. In clinical trials levosimendan improves symptoms, cardiac function, hemodynamics, and end-organ function. Adverse effects are generally less common than with other inotropic and vasoactive therapies, with the notable exception of hypotension. The decision to use levosimendan, in terms of timing and dosing, is influenced by the presence of pulmonary congestion, and blood pressure measurements. Levosimendan should be preferred over adrenergic inotropes as a first line therapy for all ACS-AHF patients who are under beta-blockade and/or when urinary output is insufficient after diuretics. Levosimendan can be used alone or in combination with other inotropic or vasopressor agents, but requires monitoring due to the risk of hypotension.

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BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan.
RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience.
CONCLUSIONS: The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.

Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS).

The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.