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Hetrombopag, a novel, oral small molecule thrombopoietin receptor agonist, exhibits an obvious thrombocytopoietic effect with good safety. Hetrombopag is currently under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). The objectives of this study were to assess the effect of high-fat and high-calorie food on the pharmacokinetic and pharmacodynamic (PK/PD) profiles of hetrombopag in healthy volunteers. An independent, single-dose, open-label, randomized-sequence, crossover trial was conducted. Healthy volunteers received hetrombopag 7.5-mg tablets in the fasted state or with a high-fat, high-calorie breakfast. The effects of the high-fat and high-calorie food on the PK/PD profiles of hetrombopag were evaluated by using a noncompartmental analysis and a semi-physiological model. Twelve Chinese healthy volunteers were enrolled. Mean plasma AUC0–t and Cmax decreased by 98.7% and 95.0%, respectively, when hetrombopag was administered with high-fat and high-calorie food. The semi-physiological PK/PD model analysis showed that the absorption rate constant at the first absorption site was almost halved at the fed condition. The change in platelet counts in the fed condition was not sufficiently as sensitive as that in the fasted condition. High-fat and high-calorie food were associated with significantly reduced systemic exposure and platelet count sensitivity. Thus, hetrombopag should be taken in a fasted state to avoid the impact of food on bioavailability and platelet counts. ClinicalTrials.gov identifier: NCT02409394. [Display omitted] •Hetrombopag is a novel and second-generation thrombopoietin receptor agonist under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP).•Concomitant administration of hetrombopag with high-fat, high-calorie food was associated with markedly reduced systemic exposure.•A semi-physiological model analysis showed that platelet counts change at fed condition seemed not sufficiently sensitive as that at the fasted condition.•The semi-physiological model did not only describe the clinical data suitably but also permitted a deeper understanding of the PK/PD relationship.

Acquired diaphragm muscle weakness is a key feature in several chronic conditions, including chronic obstructive pulmonary disease, congestive heart failure, and difficult weaning from mechanical ventilation. No drugs are available to improve respiratory muscle function in these patients. Recently, we have shown that the calcium sensitizer levosimendan enhances the force-generating capacity of isolated diaphragm fibers. To investigate the effects of the calcium sensitizer levosimendan on in vivo human diaphragm function. In a double-blind, randomized, crossover design, 30 healthy subjects performed two identical inspiratory loading tasks. After the first loading task, subjects received levosimendan (40 μg/kg bolus followed by 0.1/0.2 μg/kg/min continuous infusion) or placebo. Transdiaphragmatic pressure, diaphragm electrical activity, and their relationship (neuromechanical efficiency) were measured during loading. Magnetic phrenic nerve stimulation was performed before the first loading task and after bolus administration to assess twitch contractility. Center frequency of diaphragm electrical activity was evaluated to study the effects of levosimendan on muscle fiber conduction velocity. The placebo group showed a 9% (P=0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuro-mechanical efficiency of the diaphragm during loading improved by 21% (P<0.05) in the levosimendan group. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P<0.05). The calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure.

Calcium desensitization plays an important part in the pathophysiology of septic myocardial depression. We postulated that levosimendan, a new calcium sensitizer, would be beneficial in sepsis-induced cardiac dysfunction. Prospective, randomized, controlled study in two university hospital intensive care units. Twenty-eight patients with persisting left ventricular dysfunction related to septic shock after 48 h of conventional treatment including dobutamine (5 microg/kg per minute). After 48 h of conventional treatment patients were randomized to receive a 24-h infusion of either levosimendan (0.2 microg/kg per minute, n=15) or dobutamine (5 microg/kg per minute, n=13). Data from right heart catheterization, echocardiography, gastric tonometry, laser-Doppler flowmetry, and lactate concentrations and creatinine clearance were obtained before and after the 24-h drug infusion. Dobutamine did not change systemic or regional hemodynamic variables. By contrast, at the same mean arterial pressure levosimendan decreased pulmonary artery occlusion pressure and increased cardiac index. Levosimendan decreased left ventricular end-diastolic volume and increased left ventricular ejection fraction. Levosimendan increased gastric mucosal flow, creatinine clearance, and urinary output while it decreased lactate concentrations. These findings show that levosimendan improves systemic hemodynamics and regional perfusion in patients with septic cardiac dysfunction under conditions where administration of 5 microg/kg dobutamine per minute is no longer efficacious. Accordingly, our results suggest that levosimendan can be an alternative to the strategy of increasing the dose of dobutamine under such conditions.

Background Levosimendan is a promising new inodilator agent but its effectiveness in peripartum cardiomyopathy (PPCM) has not been tested in a clinical trial. The authors sought to evaluate the effect of levosimendan therapy and to determine the predictors of clinical outcome in patients with PPCM. Methods and results The authors prospectively randomized 24 consecutive women with PPCM. Twelve patients (control group) were randomized to conventional heart failure therapy and 12 patients (levosimendan group) were randomized to levosimendan in addition to the conventional therapy. Mean follow-up period was 20.9 ± 9 months (ranged 12–38 months). The two groups did not differ in baseline demographic and echocardiographic characteristics. Eleven patients (45.8%) recovered completely (6 in control group and 5 in levosimendan group, p  > 0.05), 6 died (25%) (3 in control group and 3 in levosimendan group), and 7 (29.1%) were left with persistent left ventricular dysfunction (PLVD) (3 in control group and 4 in levosimendan group, p  > 0.05). There were significant differences in baseline characteristics between deceased patients and survivors including left ventricular end-diastolic diameter (7.1 ± 0.6 vs. 6.4 ± 0.5 cm, p  = 0.031), left ventricular end-systolic diameter (LVESD) (6.4 ± 0.8 vs. 5.5 ± 0.6 cm, p  = 0.027), left ventricular ejection fraction (LVEF) (19.7 vs. 27.4%, p  = 0.025), and left atrial diameter (4.9 ± 0.3 vs. 4.3 ± 0.4 cm, p  = 0.011). Conclusions Addition of levosimendan to conventional therapy did not improve outcome in patients with PPCM. In patients with PLVD or patients who died, LVEF, LVESD and left atrial diameter were worse than those with complete resolution.

Septic shock is the leading causes of death in intensive care units. In addition to generous fluid administration, inotropic agents are commonly used to improve cardiac output. The effects of inotropic agents on regional blood flow remains unknown. The aim of this study was to assess the effects of levosimendan vs dobutamine added to dopamine on liver functions assessed using noninvasive liver function monitoring (LiMON) in patients with septic shock. Prospective analysis. We analyzed 30 patients with septic shock who were treated in an intensive care unit. Indocyanine green plasma disappearance rate (ICG-PDR) was conducted concurrently using the LiMON system. A dose of 0.3 mg/kg ICG was given through a cubital fossa vein as a bolus. Statistical analysis showed that the variation of hemodynamic variables was different between groups. In our results, the increase in systolic blood pressure, diastolic blood pressure, and mean arterial pressure was significantly higher in levosimendan group than in dobutamine group (P < .05). There was a decrease in before- and after-infusion ICG-PDR values in dobutamine group (20.38 ± 4.83 vs 20.34 ± 5.30), and no statistical difference was detected (P = .649). There was an increase in before- and after-infusion ICG-PDR values in levosimendan group (18.70 ± 2.59 vs 21.65 ± 3.20), and a statistical difference was detected (P = .001). There was statistical difference between groups (P = .000). These results suggest that levosimendan added to dopamine improves systemic hemodynamics and increases splanchnic perfusion assessed using the user-friendly noninvasive bedside system LiMON in patients with septic shock compared with dobutamine.

Liver dysfunction due to a low cardiac output state after cardiac surgery is associated with a poor prognosis, but whether one inotrope is superior to another in improving hepatic perfusion remains uncertain. This study compared the systemic and hepatic haemodynamic effects of levosimendan to dobutamine in patients with a low cardiac output state (cardiac index < 2.2 l/min/m2) after on-pump cardiac surgery. A total of 25 patients were randomised to receive either an intravenous bolus of levosimendan (12 µg/kg) over 15 minutes, followed by an infusion of 0.2 µg/kg/min for 24 hours, or an infusion of dobutamine 7.5 µg/kg/min for 24 hours and completed the study. The systemic and hepatic haemodynamics at 24 and 48 hours were all better after levosimendan than dobutamine (dobutamine group: cardiac index (l/min/m2)=2.51 [standard deviation ±0.29], 2.40±0.23; portal vein flow (ml/min): 614.0±124.7, 585.9±144.8; pulsatility index: 2.02±0,28, 2.98±0.27 versus the levosimendan group: cardiac index: 3.02± 0.27, 2.98± 0.30; portal vein flow: 723.0± 143.5, 702.9±117.8; pulsatility index: 1.71±0.26, 1.73±0.27). The improvement in portal vein blood flow at 48 hours was significantly better after levosimendan than dobutamine (41% vs. 11% increment from baseline, P<0.05). In addition, there was a significant reduction in hepatic artery resistance after levosimendan but not dobutamine (resistance index reduction 6.5% vs. 0%, P<0.05). In summary, levosimendan can be considered as a selective liver vasodilator and can improve hepatic blood flow through both the hepatic artery and portal venous system, whereas dobutamine can only improve the portal venous blood flow without vasodilating the hepatic artery.

Levosimendan is a relatively new cardiac inotropic agent with calcium sensitizing activity. This study was conducted to investigate the effects of levosimendan (L) and dobutamine (D) on renal function in patients hospitalized with decompensated heart failure (HF). The present study included 88 consecutive patients hospitalized with acutely decompensated HF (New York Heart Association (NYHA) Class 3-4) requiring inotropic therapy. Patients were randomized 2:1 to either L or D for intravenous inotropic support. Diuretic therapy was kept constant during infusions. Renal function values, including serum creatinine (CR), blood urea nitrogen, 24-h urinary output levels and calculated glomerular filtration rate (GFR) were measured just prior to and 24 h after the infusions in all patients, and 48 and 72 h after the infusions in every second patient in both groups. The pre and post-infusion values of renal function and left ventricular ejection fraction (LVEF) were evaluated. LVEF increased significantly in both groups. Those in L showed a significant improvement in calculated GFR after 24 h, whereas those in D showed no significant change (median in change in L:+15.3%, median change in D: -1.33%). Furthermore, in the L group a significant improvement was observed in calculated GFR after 72 h compared to baseline levels, whereas in D no significant change (median change in L:+45.45%, median change in D: +0.09%) was seen. Both agents improved 24-h urinary output. Levosimendan seems to provide beneficial effects in terms of improvement in renal function compared to dobutamine in patients with heart failure who require inotropic therapy.

Hetrombopag (Hengqu ® ), an oral nonpeptide thrombopoietin receptor agonist, is being developed by Jiangsu Hengrui Pharmaceutical for the treatment of thrombocytopenia and aplastic anaemia. On 16 June 2021, hetrombopag received its first approval in China as a second-line treatment for primary immune thrombocytopenia (ITP) and severe aplastic anaemia (SAA) in adults. The drug is also undergoing phase III development in China for the treatment of chemotherapy-induced thrombocytopenia. This article summarizes the milestones in the development of hetrombopag leading to this first approval for ITP and SAA.

During the last five decades, a large number of BT (Benzothiazole) derivatives formed one of the eligible structures in medicinal chemistry as anticancer agents. Most of the studies reveal that various substitutions at specific positions on BT scaffold modulate the antitumor property. The potential of BTs encouraged us to synthesize a number of new 2-((5-substitutedbenzothiazol-2-yl)thio)-N’-(2-(4-(substitutedphenyl)ethylidene)acetohydrazide derivatives and investigate their probable anticancer activity. 4-Substitued benzaldehyde derivatives (1a–1e) were afforded by the reaction of appropriate secondary amine and 4-fluorobenzaldehyde in DMF. Equimolar quantitates of 5-substitutedbenzothiazole-2-thiol, ethyl chloroacetate and K2CO3 were refluxed in acetone to obtain 2-((5-substitutedbenzothiazol-2-yl)thio)acetate derivatives (2a,2b), which reacted with excess of hydrazine hydrate to get 2-((5-substitutebenzothiazol-2-yl)thio)acetohydrazides (3a,3b). In the last step, 2-((5-substitutedbenzothiazol-2-yl)thio)-N’-(4-substitutedbenzylidene)acetohydrazide derivatives (4a–4j) were synthesized by the reaction of 1a–1e and 3a–3b in EtOH. The anticancer activity of target compounds was evaluated in three steps. First, an MTT test (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was performed to observe cytotoxic activity of the compounds against carcinogenic C6 (Rat brain glioma cell line), A549 (Human lung adenocarcinoma epithelial cell line), MCF-7 (Human breast adenocarcinoma cell line), and HT-29 (Human colorectal adenocarcinoma cell line) cancer cell lines. Healthy NIH3T3 (Mouse embryo fibroblast cell line) cells were also subjected to MTT assay to determine selectivity of the compounds towards carcinogenic cell lines. Secondly, inhibitory effects of selected compounds 4d, 4e, and 4h on DNA synthesis of C6 cells were investigated. Finally, flow cytometric analysis were performed to identify the death pathway of the carcinogenic cells.

Pain and inflammation are unpleasant experiences that usually occur as a result of tissue damage. Despite the number of existing analgesic drugs, side effects limit their use, stimulating the search for new therapeutic agents. In this sense, five hydrazone derivatives (H1, H2, H3, H4, and H5), with general structure R 1 R 2 C = NNR 3 R 4 , were synthesized with molecular modification strategies. In this paper, we describe the ability of hydrazone derivatives to attenuate nociceptive behavior and the inflammatory response in mice. Antinociceptive activity was evaluated through acetic acid-induced writhing and formalin-induced nociception tests. In both experimental models, the hydrazone with the greatest potency (H5) significantly ( p < 0.05) reduced nociceptive behavior. Additionally, methods of acute and chronic inflammation induced by different chemicals (carrageenan and histamine) were performed to evaluate the anti-inflammatory effect of H5. Moreover, molecular docking analysis revealed that H5 can block the COX-2 enzyme, reducing arachidonic acid metabolism and consequently decreasing the production of prostaglandins, which are important inflammatory mediators. H5 also changes locomotor activity. In summary, H5 exhibited relevant antinociceptive and anti-inflammatory potential and acted on several targets, making it a candidate for a new multi-target oral anti-inflammatory drug.