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Molecular interaction study of an anticancer drug, ponatinib with human serum albumin using spectroscopic and molecular docking methods

Tayyab S, Sam SE, Kabir MZ, Ridzwan NFW, Mohamad SB

Spectrochim Acta A Mol Biomol Spectrosc, 2019 May 05;214:199-206.
PMID: 30780089 DOI: 10.1016/j.saa.2019.02.028

Binding of a potent anticancer agent, ponatinib (PTB) to human serum albumin (HSA), main ligand transporter in blood plasma was analyzed with several spectral techniques such as fluorescence, absorption and circular dichroism along with molecular docking studies. Decrease in the KSV value with increasing temperature pointed towards PTB-induced quenching as the static quenching, thus affirming complexation between PTB and HSA. An intermediate binding affinity was found to stabilize the PTB-HSA complex, as suggested by the Ka value. Thermodynamic analysis of the binding phenomenon revealed participation of hydrophobic and van der Waals interactions along with hydrogen bonds, which was also supported by molecular docking analysis. Changes in both secondary and tertiary structures as well as in the microenvironment around Trp and Tyr residues of HSA were anticipated upon PTB binding to the protein, as manifested from circular dichroism and three-dimensional fluorescence spectra, respectively. Binding of PTB to HSA led to protein's thermal stabilization. Competitive ligand displacement experiments using different site markers such as warfarin, indomethacin and ketoprofen disclosed the binding site of PTB as Sudlow's site I in HSA, which was further confirmed by molecular docking analysis.

Matched MeSH terms: Pyridazines/chemistry*
Fulltext Rechallenge of ponatinib in chronic myeloid leukaemia after hepatotoxicity

Boo YL, Liam CCK, Toh SG, Lim SM

Hong Kong Med J, 2019 04;25(2):162-163.
PMID: 30971509 DOI: 10.12809/hkmj187420
Matched MeSH terms: Pyridazines/adverse effects; Pyridazines/therapeutic use*
Fulltext Coughing Shih Tzu dog due to myxomatous mitral valve disease stage C2

Khor, K.H., Jessie-Bay, J.X.

Jurnal Veterinar Malaysia, 2018;30(1):15-19.
MyJurnal

Myxomatous Mitral Valve Disease is a degenerative condition of the mitral valves leaflets. A 10-year-old
male castrated Shih Tzu was presented with primary complaint of coughing. Clinical examination revealed normal
heart rate, respiratory rate and rectal temperature. Systolic murmur Grade IV/VI was heard at the left heart apex.
Thoracic radiographic findings were cardiomegaly with the vertebral heart score of 11.0 and had evidence of
cardiogenic pulmonary edema. Echocardiographic examination revealed thickening mitral valves with evidence of
moderate regurgitation observed. Based on the findings obtained, the dog was diagnosed with Myxomatous Mitral
Valve disease stage C2. Dog was treated with benazepril (0.5mg/kg), pimobendan (0.2mg/kg) with a combination of
furosemide (2mg/kg). Frusemide was gradually removed from the treatment regime as coughing improved over time.
The dog was no longer lethargy and even gained weight.

Matched MeSH terms: Pyridazines
Role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke exposure induced cognitive impairment in Danio rerio

Muthuraman A, Nafisa K, Sowmya MS, Arpitha BM, Choedon N, Sandy CD, et al.

Life Sci, 2019 Mar 04.
PMID: 30844374 DOI: 10.1016/j.lfs.2019.03.002

BACKGROUND: Cigarette smoke is exogenous modifiable factors to changes the neurovascular complication. The chronic exposure of cigarette smoke enhances neurocognitive dysfunction.
AIMS: The present study is focused on evaluating the role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke-induced cognitive impairment in Danio rerio.
MAIN METHODS: The cognitive dysfunction was developed by cigarette smoke exposure (CSE; 10 min in 25 ml of CSE per day) for five days. The selective endothelin-A receptor antagonist i.e., ambrisentan (2.5 to 5 mg/kg; i.p. for five consecutive days) was used for testing of CSE induced cognitive dysfunction. In addition, treatment of reference drug i.e., donepezil (10 mg/kg; i.p. for five consecutive days) was used for this cognitive function study. The cognitive functions were assessed by light and dark chamber; color recognition; partition preference; horizontal compartment; and T-Maze tests. Further, the CSE induced biomarkers changes of the zebrafish brain samples were estimated.
KEY FINDINGS: The treatment of ambrisentan showed a potential ameliorative effect against the CSE induced cognitive functions along with attenuation of biochemical changes. The results are comparable to donepezil-treated groups.
SIGNIFICANCE: Therefore, ambrisentan can be considered for the attenuation of CSE induced impairment neurocognitive functions due to its reduction of free radical scavenging and neuroinflammatory actions as well as regulation of cholinergic neurotransmitter functions.

Matched MeSH terms: Pyridazines
A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design

Zangrillo A, Alvaro G, Pisano A, Guarracino F, Lobreglio R, Bradic N, et al.

Am Heart J, 2016 Jul;177:66-73.
PMID: 27297851 DOI: 10.1016/j.ahj.2016.03.021

OBJECTIVE: Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes.
DESIGN: Double-blind, placebo-controlled, multicenter randomized trial.
SETTING: Tertiary care hospitals.
INTERVENTIONS: Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours.
MEASUREMENTS AND MAIN RESULTS: The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction.
CONCLUSIONS: This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.

Matched MeSH terms: Pyridazines/therapeutic use*
Fulltext Myxomatous mitral valve disease in a Shih Tzu dog

Teoh, Y.B., Khor, K.H.

Jurnal Veterinar Malaysia, 2017;29(1):18-22.
MyJurnal

An 11-year-old intact male Shih Tzu dog was referred to the University Veterinary Hospital (UVH) with history of coughing and laboured breathing. Auscultation revealed that the dog had a left systolic heart murmur grade V/VI at the base of the heart. Radiography showed findings of cardiomegaly and pulmonary oedema. Echocardiography findings revealed that dog has a myxomatous mitral valve disease. The mitral valve was severely thickened and prolapsed into the left atrium. Congestive heart failure (CHF) was treated with an angiotensin converting enzyme (ACE) inhibitor and diuretic. An anti-mucolytic agent was prescribed as a symptomatic treatmentfor the coughing that could be due to mild bronchitis. Dog did not response well with treatment as the frequency of cough was not reduced and the duration was longer each time. Pimobendan was then added on to the initial treatment and there was a tremendous improvement seen from the patient after that. Episodes of productive cough were noticed greatly reduced and dog was much more active at home post two weeks of ACE inhibitor, diuretic and dual-acting inodilator. We successfully maintained the dog with minimal coughing episodes. However, the prognosis is moderate to poor in this case due to possibilities of refraction towards medications.

Matched MeSH terms: Pyridazines