scholarly journals Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

2020 ◽  
Vol 21 (24) ◽  
pp. 9599
Author(s):  
Khulud Alsulami ◽  
Steven Marston
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Pathological Condition ◽  
Treatment Options ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Phase Iii ◽  
Extensive Literature ◽  
Therapeutic Value ◽  
Omecamtiv Mecarbil

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as “recouplers” was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development.

scholarly journals A Cellular Assay for the Identification and Characterization of Connexin Gap Junction Modulators

2021 ◽  
Vol 22 (3) ◽  
pp. 1417
Author(s):  
Azeem Danish ◽  
Robin Gedschold ◽  
Sonja Hinz ◽  
Anke C. Schiedel ◽  
Dominik Thimm ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Small Molecules ◽  
High Throughput Screening ◽  
Cell Communication ◽  
Receptor Activation ◽  
Adenosine A2a Receptor ◽  
Intracellular Camp ◽  
Donor Cells ◽  
A2a Receptor ◽  
Adenosine A2a

Connexin gap junctions (Cx GJs) enable the passage of small molecules and ions between cells and are therefore important for cell-to-cell communication. Their dysfunction is associated with diseases, and small molecules acting as modulators of GJs may therefore be useful as therapeutic drugs. To identify GJ modulators, suitable assays are needed that allow compound screening. In the present study, we established a novel assay utilizing HeLa cells recombinantly expressing Cx43. Donor cells additionally expressing the Gs protein-coupled adenosine A2A receptor, and biosensor cells expressing a cAMP-sensitive GloSensor luciferase were established. Adenosine A2A receptor activation in the donor cells using a selective agonist results in intracellular cAMP production. The negatively charged cAMP migrates via the Cx43 gap junctions to the biosensor cells and can there be measured by the cAMP-dependent luminescence signal. Cx43 GJ modulators can be expected to impact the transfer of cAMP from the donor to the biosensor cells, since cAMP transit is only possible via GJs. The new assay was validated by testing the standard GJ inhibitor carbenoxolon, which showed a concentration-dependent inhibition of the signal and an IC50 value that was consistent with previously reported values. The assay was demonstrated to be suitable for high-throughput screening.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

scholarly journals A pebble clogging a river: a case report of thrombosed coronary aneurysmal ectasia

2020 ◽  
Author(s):  
Akshar Jaglan ◽  
Tarek Ajam ◽  
Steven C Port ◽  
Tanvir Bajwa ◽  
A Jamil Tajik
Keyword(s):  
Acute Coronary Syndrome ◽  
Coronary Artery ◽  
Kawasaki Disease ◽  
Treatment Options ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Coronary Artery Ectasia ◽  
Ventricular Ejection Fraction ◽  
Coronary Syndrome ◽  
Patient Reported

Abstract Background Coronary artery ectasia (CAE) is a rare anomaly that can present at any age. Predisposing risk factors include Kawasaki disease in a younger population and atherosclerosis in the older generation. We present a unique case of the management of a young woman diagnosed with multivessel CAE with aneurysmal changes in the setting of acute coronary syndrome and subsequently during pregnancy. Case summary A 23-year-old woman presented with acute onset chest pain. Electrocardiogram revealed no ischaemic changes; however, troponin I peaked at 16 ng/mL (reference range 0–0.04 ng/mL). Echocardiogram showed apical dyskinesis with preserved left ventricular ejection fraction. Coronary angiography showed multivessel CAE along with significant thrombus burden in an ectatic lesion of the left anterior descending artery. Since the patient was haemodynamically stable, conservative management with dual antiplatelet therapy and anticoagulation was started. On follow-up, coronary computed tomographic angiogram illustrated resolution of the coronary thrombi and echocardiogram showed improvement to the apical dyskinesis. It was presumed that Kawasaki disease was the most likely aetiology of her disease. Subsequently the patient reported that, contrary to medical advice, she was pregnant, adding another layer of complexity to her case. Discussion Coronary artery ectasia can be discovered as an incidental finding or can present with an acute coronary syndrome. Management is challenging in the absence of randomized trials and large-scale data. Treatment options include medications, percutaneous intervention, and surgical revascularization. Close surveillance is required in these patients to assess progression of disease. Here we discuss treatment options during acute coronary syndrome and pregnancy.

scholarly journals Therapeutic Advances in Oncology

2021 ◽  
Vol 22 (4) ◽  
pp. 2008
Author(s):  
Jinsha Liu ◽  
Priyanka Pandya ◽  
Sepideh Afshar
Keyword(s):  
Small Molecules ◽  
New Technologies ◽  
Treatment Options ◽  
Current Treatment ◽  
Bispecific Antibodies ◽  
Gene Therapies ◽  
Therapeutic Modalities ◽  
The Past ◽  
Drug Conjugates ◽  
Novel Targets

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.

scholarly journals A High Throughput Screening Assay for Anti-Mycobacterial Small Molecules Based on Adenylate Kinase Release as a Reporter of Cell Lysis

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0129234 ◽  
Author(s):  
Lauren Forbes ◽  
Katherine Ebsworth-Mojica ◽  
Louis DiDone ◽  
Shao-Gang Li ◽  
Joel S. Freundlich ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput ◽  
Adenylate Kinase ◽  
High Throughput Screening ◽  
Cell Lysis ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Adenylate Kinase Release

scholarly journals Urinary Excretion of Phenolic Acids by Infants and Children: A Randomised Double-Blind Clinical Assay

2012 ◽  
Vol 6 ◽  
pp. CMPed.S9349
Author(s):  
J. Uberos ◽  
V. Fernéndez-Puentes ◽  
M. Molina-Oya ◽  
R. Rodrïguez-Belmonte ◽  
A. Ruïz-López ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Ferulic Acid ◽  
Phenolic Acids ◽  
Treatment Options ◽  
Randomised Clinical Trial ◽  
Phase Iii ◽  
Double Blind ◽  
Clinical Assay ◽  
Increased Risk ◽  
Study Population

Objectives The present study, which is part of the ISRCTN16968287 clinical assay, is aimed at determining the effects of cranberry syrup or trimethoprim treatment for UTI. Methods This Phase III randomised clinical trial was conducted at the San Cecilio Clinical Hospital (Granada, Spain) with a study population of 192 patients, aged between 1 month and 13 years. Criteria for inclusion were a background of recurrent UTI, associated or otherwise with vesico-ureteral reflux of any degree, or renal pelvic dilatation associated with urinary infection. Each child was randomly given 0.2 mL/Kg/day of either cranberry syrup or trimethoprim (8 mg/mL). The primary and secondary objectives, respectively, were to determine the risk of UTI and the levels of phenolic acids in urine associated with each intervention. Results With respect to UTI, the cranberry treatment was non-inferior to trimethoprim. Increased urinary excretion of ferulic acid was associated with a greater risk of UTI developing in infants aged under 1 year (RR 1.06; CI 95% 1.024–1.1; P = 0.001). Conclusions The results obtained show the excretion of ferulic acid is higher in infants aged under 1 year, giving rise to an increased risk of UTI, for both treatment options.

In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules

2014 ◽  
Vol 19 (11) ◽  
pp. 1721-1730 ◽  
Author(s):  
Sarah S.W. Wong ◽  
Lakshman P. Samaranayake ◽  
Chaminda J. Seneviratne
Keyword(s):  
Small Molecules ◽  
High Throughput ◽  
Antifungal Agent ◽  
High Throughput Screening ◽  
Candida Infections ◽  
The Ideal

scholarly journals Pursuing the non-invasive assessment of cardiac contractility: the added value of pressure-area-strain loop analysis in volume overload-induced heart failure

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
M Tokodi ◽  
BK Lakatos ◽  
M Ruppert ◽  
A Olah ◽  
AA Sayour ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitral Valve ◽  
Cardiac Contractility ◽  
Volume Overload ◽  
Left Ventricular ◽  
Stroke Work ◽  
Loading Conditions ◽  
Innovation And Technology ◽  
Pressure Area ◽  
Area Strain

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the New National Excellence Programme (ÚNKP-19-3-I) of the Ministry for Innovation and Technology in Hungary, and the Artificial Intelligence Research Field Excellence Programme of the National Research, Development and Innovation Office of the Ministry of Innovation and Technology in Hungary. Background Global longitudinal strain (GLS) by speckle-tracking echocardiography (STE) is a sensitive parameter of left ventricular (LV) systolic function. Nevertheless, GLS is dependent on loading conditions. Through the analysis of pressure-strain loops, myocardial work was recently introduced and tested in different clinical scenarios. Myocardial work incorporates afterload, but still, it neglects changes in preload and LV geometry. Purpose Accordingly, our aim was to test our hypothesis that adding instantaneous LV size to myocardial work calculation can further mitigate the load-dependency of GLS, and therefore, a better correlation with intrinsic myocardial contractility can be achieved. Methods Volume overload-induced heart failure was established by an aortocaval fistula (ACF) in male Wistar rats (n = 12). Age-matched sham-operated animals served as controls (n = 12). STE was performed to assess GLS, which was immediately followed by invasive pressure-volume (P-V) analysis to assess LV pressure and to compute a gold-standard index of cardiac contractility (preload recruitable stroke work [PRSW]). Global myocardial work index (GMWI) was calculated from GLS and the invasively measured LV pressure. To compute GMWI indexed to LV area (GMWIA), the instantaneous power (calculated by multiplying the strain rate and the instantaneous LV pressure) was divided by the instantaneous LV area, and then it was integrated from mitral valve closure until mitral valve opening. Results LV ejection fraction did not differ significantly (ACF vs. controls: 59 ± 4 vs. 65 ± 9%, p = NS), whereas GLS (Figure 1A - representative animals) was slightly decreased in the ACF group (-13.2 ± 2.3 vs. -15.4 ± 1.9%, p < 0.05). In contrast, PRSW, GMWI (Figure 1B - representative animals) and GMWIA (Figure 1C - representative animals) were considerably reduced in ACF compared to controls (57 ± 13 vs. 111 ± 38mmHg, 1383 ± 382 vs. 1928 ± 281mmHg%, 11.6 ± 3.7 vs. 47.9 ± 22.8mmHg%/mm2, all p < 0.01). GLS showed moderate correlation with PRSW (r=-0.550, p < 0.01), whereas GMWI correlated more significantly, but still moderately with the invasively measured LV contractility (r = 0.681, p < 0.001). Correlation between the pressure-area-strain loop-derived GMWIA and P-V analysis-derived PRSW (Figure 1D) was found to be very strong (r = 0.924, p < 0.001). Conclusions In the case of LV volume overload-induced heart failure, our pressure-area-strain loop-derived metric reflected LV contractility better than GLS and even GMWI. Therefore, the incorporation of instantaneous LV size into myocardial work calculation represents a promising clinical tool to assess and monitor intrinsic myocardial function independently of loading conditions. Abstract Figure 1

Abstract 276: The Regulatory Effects Of Peroxiredoxin II On Phospholamban Phosphorylation And Cardiac Contractile Function In Vivo

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Wen Zhao ◽  
Xiaojing Shi ◽  
Wenjuan Zhou ◽  
Huimin Wang ◽  
Xuepeng Geng ◽  
...  
Keyword(s):  
Cardiac Contractility ◽  
Left Ventricular ◽  
Active Inhibitor ◽  
Rat Cardiomyocytes ◽  
Cardiac Contractile ◽  
Adenoviral Delivery ◽  
Anti Oxidant ◽  
Contraction And Relaxation ◽  
Phospholamban Phosphorylation

Peroxiredoxin II (prxII), a cytosolic form of the anti-oxidant peroxiredoxin family, was recently found to be decreased in failing human hearts. Interestingly, in hyperdynamic hearts of two genetically modified mouse models with: a) phospholamban ablation; and b) overexpression of the active inhibitor-1 of protein phosphatase 1, the levels of this cellular peroxidase (prxII) were markedly increased. Acute overexpression of prxII by adenoviral-delivery in adult rat cardiomyocytes (Ad-prxII) was associated with decreases in the basal rates of contraction and relaxation, as well as calcium kinetics. Accordingly, Ad-prxII-AS infected cardiomyocytes exhibited enhanced contractile parameters and Ca-kinetics. The depressed or increased contractility by Ad-prxII or Ad-prxII-AS was associated with parallel decreases or increases in phosphorylation of phospholamban (Ser16 and Thr17). To determine the in vivo effects of prxII on cardiac contractility, three transgenic lines (TG) with 2-3 fold cardiac-specific overexpression of prxII were generated and their cardiac morphologic and functional phenotypes were characterized. The TG mice exhibited no alterations in cardiac pathology or morphology up to 4 months of age. However, langendorf perfusions revealed that cardiac contractility, including the rates of contraction and relaxation (±dp/dtmax) as well as the left ventricular end systolic pressure (LVESP), were significantly depressed in TG mice (to 75, 76 and 63%, respectively), compared to WTs (100%). The depressed function was not associated with any alterations in the expression levels of key SR calcium handling proteins: SERCA2, total phospholamban, calsequestrin and ryanodine receptor. However, the levels of the phosphorylated PLN at Ser16 were found to be reduced to 50% in the TG mice, compared to WTs. These findings indicate that prxII, an anti-oxidant protein, may regulate basal cardiac contractile performance in vivo through phospholamban phosphorylation.

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