Effect of a Perioperative Hypotension-Avoidance Strategy Versus a Hypertension-Avoidance Strategy on the Risk of Acute Kidney Injury: A Clinical Research Protocol for a Substudy of the POISE-3 Randomized Clinical Trial

Background: Most patients who take antihypertensive medications continue taking them on the morning of surgery and during the perioperative period. However, growing evidence suggests this practice may contribute to perioperative hypotension and a higher risk of complications. This protocol describes an acute kidney injury substudy of the Perioperative Ischemic Evaluation-3 (POISE-3) trial, which is testing the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy in patients undergoing noncardiac surgery. Objective: To conduct a substudy of POISE-3 to determine whether a perioperative hypotension-avoidance strategy reduces the risk of acute kidney injury compared with a hypertension-avoidance strategy. Design: Randomized clinical trial with 1:1 randomization to the intervention (a perioperative hypotension-avoidance strategy) or control (a hypertension-avoidance strategy). Intervention: If the presurgery systolic blood pressure (SBP) is <130 mmHg, all antihypertensive medications are withheld on the morning of surgery. If the SBP is ≥130 mmHg, some medications (but not angiotensin receptor blockers [ACEIs], angiotensin receptor blockers [ARBs], or renin inhibitors) may be continued in a stepwise manner. During surgery, the patients’ mean arterial pressure (MAP) is maintained at ≥80 mmHg. During the first 48 hours after surgery, some antihypertensive medications (but not ACEIs, ARBs, or renin inhibitors) may be restarted in a stepwise manner if the SBP is ≥130 mmHg. Control: Patients receive their usual antihypertensive medications before and after surgery. The patients’ MAP is maintained at ≥60 mmHg from anesthetic induction until the end of surgery. Setting: Recruitment from 108 centers in 22 countries from 2018 to 2021. Patients: Patients (~6800) aged ≥45 years having noncardiac surgery who have or are at risk of atherosclerotic disease and who routinely take antihypertensive medications. Measurements: The primary outcome of the substudy is postoperative acute kidney injury, defined as an increase in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of randomization or ≥50% within 7 days of randomization. Methods: The primary analysis (intention-to-treat) will examine the relative risk and 95% confidence interval of acute kidney injury in the intervention versus control group. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by preexisting chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate <60 mL/min/1.73 m2. Results: Substudy results will be analyzed in 2022. Limitations: It is not possible to mask patients or providers to the intervention; however, objective measures will be used to assess acute kidney injury. Conclusions: This substudy will provide generalizable estimates of the effect of a perioperative hypotension-avoidance strategy on the risk of acute kidney injury.

Combined Ligand and Structure Based Approaches Towards Developing Novel Renin Inhibitors for the Treatment of Hypertension

<p>Hypertension is considered as the predominant risk factor for the onset of Cardiovascular disease (CVD) in the elder population. The chronic activation of Renin Angiotensin System (RAS) is considered as the primary causative factor for the inception of hypertension in geriatric population. Angiotensin Converting Enzyme (ACE) is a highly explored druggable target in the context of hypertension since this enzyme catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. But clinical trials conducted on ACE inhibitors reported their incompetence in the effective treatment of hypertension. Hence, recent studies are focussing on renin, which is a central component of RAS in the regulation of blood pressure. The present study focuses on the elucidation of physicochemical properties of chemical compounds essential for renin inhibition and identification of novel renin inhibitors possessing enhanced potency as well as bioavailability. We have employed Molecular Field Topology Analysis (MFTA) as well as Structure Based Drug Design (SBDD) approaches for the accomplishment of above-mentioned objectives. MFTA approach were piloted on 45 indole-3-carboxamide derivatives by elucidating the significance of charge distribution as well as molecular size of chemical species in eliciting renin inhibition. Optimal model was obtained with Nf = 3, r²= 0.81 , Q² = 0.65. Molecular docking, atom-based binding free energy contributions and bioavailability assessments were carried out to identify most potent lead molecule among 45 compounds reported for renin inhibition. Further, new derivative molecules were predicted for the best lead molecule by employing chemical space exploration. All datasets, descriptor values, QSAR models for predictions usage and plots will be available in <a href="https://github.com/giribio/agingdata">https://github.com/giribio/agingdata</a></p><p></p>

Combined Ligand and Structure Based Approaches Towards Developing Novel Renin Inhibitors for the Treatment of Hypertension

<p>Hypertension is considered as the predominant risk factor for the onset of Cardiovascular disease (CVD) in the elder population. The chronic activation of Renin Angiotensin System (RAS) is considered as the primary causative factor for the inception of hypertension in geriatric population. Angiotensin Converting Enzyme (ACE) is a highly explored druggable target in the context of hypertension since this enzyme catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. But clinical trials conducted on ACE inhibitors reported their incompetence in the effective treatment of hypertension. Hence, recent studies are focussing on renin, which is a central component of RAS in the regulation of blood pressure. The present study focuses on the elucidation of physicochemical properties of chemical compounds essential for renin inhibition and identification of novel renin inhibitors possessing enhanced potency as well as bioavailability. We have employed Molecular Field Topology Analysis (MFTA) as well as Structure Based Drug Design (SBDD) approaches for the accomplishment of above-mentioned objectives. MFTA approach were piloted on 45 indole-3-carboxamide derivatives by elucidating the significance of charge distribution as well as molecular size of chemical species in eliciting renin inhibition. Optimal model was obtained with Nf = 3, r²= 0.81 , Q² = 0.65. Molecular docking, atom-based binding free energy contributions and bioavailability assessments were carried out to identify most potent lead molecule among 45 compounds reported for renin inhibition. Further, new derivative molecules were predicted for the best lead molecule by employing chemical space exploration. All datasets, descriptor values, QSAR models for predictions usage and plots will be available in <a href="https://github.com/giribio/agingdata">https://github.com/giribio/agingdata</a></p><p></p>

Systematic study and research investigation of the use of antihypertensive drugs in the treatment of ischemic and vascular health problems

In the context of the master’s thesis a systematic investigation of the use of angiotensin II antagonists, angiotensin converting enzyme inhibitors and renin inhibitors in the treatment of hypertension (mechanism of action, duration of action, combination with other drugs), as well as a epidemiologic study of the use of these antihypertensive drugs and statistical analysis of the use of drugs from patients with ischemic and vascular health problems in a community Pharmacy and compared with large Clinical Trials.

Drug repurposing using similarity-based target prediction, docking studies and scaffold hopping of lefamulin

Aim: To investigate and validate the potential target proteins for drug repurposing of newly FDA approved antibacterial drug. Background: Drug repurposing is the process of assigning indications for drugs other than the one(s) that they were initially developed for. Discovery of entirely new indications from already approved drugs is highly lucrative as it minimizes the pipeline of the drug development process by reducing time and cost. In silico driven technologies made it possible to analyze molecules for different target proteins which are not yet explored. Objective: To analyze possible targets proteins for drug repurposing of lefamulin and their validation. Also, in silico prediction of novel scaffolds from lefamulin has been performed for assisting medicinal chemists in future drug design. Methods: A similarity-based prediction tool was employed for predicting target protein and further investigated using docking studies on PDB ID: 2V16. Besides, various in silico tools were employed for prediction of novel scaffolds from lefamulin using scaffold hopping technique followed by evaluation with various in silico parameters viz., ADME, synthetic accessibility and PAINS. Results: Based on the similarity and target prediction studies, renin is found as the most probable target protein for lefamulin. Further, validation studies using docking of lefamulin revealed the significant interactions of lefamulin with the binding pocket of the target protein. Also, three novel scaffolds were predicted using scaffold hopping technique and found to be in the limit to reduce the chances of drug failure in the physiological system during the last stage approval process. Conclusion: To encapsulate the future perspective, lefamulin may assist in the development of the renin inhibitors and, also three possible novel scaffolds with good pharmacokinetic profile can be developed into both as renin inhibitors and for bacterial infections.