An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides.

Solvent shielding of the amide hydrogen bond donor (NH groups) through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. We demonstrate that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor (>C = O) through a thioamide substitution (>C = S). The membrane permeability is a consequence of the lower desolvation penalty of the macrocycle resulting from a concerted effect of conformational restriction, local desolvation of the thioamide bond, and solvent shielding of the amide NH groups. The enhanced permeability and metabolic stability on thioamidation improve the bioavailability of a macrocyclic peptide composed of hydrophobic amino acids when administered through the oral route in rats. Thioamidation of a bioactive macrocyclic peptide composed of polar amino acids results in analogs with longer duration of action in rats when delivered subcutaneously. These results highlight the potential of O to S substitution as a stable backbone modification in improving the pharmacological properties of peptide macrocycles.

Netarsudil monotherapy as the initial treatment for open-angle glaucoma and ocular hypertension in Indian patients: A real-world evaluation of efficacy and safety.

Purpose: Glaucoma is the second leading cause of blindness worldwide, affecting more than 64 million people aged 40-80. The best way to manage primary open-angle glaucoma (POAG) is by lowering the intraocular pressure (IOP). Netarsudil is a Rho kinase inhibitor, the only class of antiglaucoma medications that reorganizes the extracellular matrix to improve the aqueous outflow through the trabecular pathway. Methods: An open-label, real-world, multicentric, observation-based 3-month study was performed for assessing the safety and ocular hypotensive efficacy of netarsudil ophthalmic solution (0.02% w/v) in patients with elevated IOP. Patients were given netarsudil ophthalmic solution (0.02% w/v) as a first-line therapy. Diurnal IOP measurements, best-corrected visual acuity, and adverse event assessments were recorded at each of the five visits (Day-1: screening day and first dosing day; subsequent observations were taken at 2 weeks, 4 weeks, 6 weeks, and 3 months). Results: Four hundred and sixty-nine patients from 39 centers throughout India completed the study. The mean IOP at baseline of the affected eyes was 24.84 ± 6.39 mmHg (mean ± standard deviation). After the first dose, the IOP was measured after 2, 4, and 6 weeks, with the final measurement taken at 3 months. The percentage reduction in IOP in glaucoma patients after 3 months of once-daily netarsudil 0.02% w/v solution use was 33.34%. The adverse effects experienced by patients were not severe in the majority of cases. Some adverse effects observed were redness, irritation, itching, and others, but only a small number of patients experienced severe reactions, as reported in a decreasing order: redness > irritation > watering > itching > stinging > blurring. Conclusion: We found that netarsudil 0.02% w/v solution monotherapy when used as the first-line treatment in primary open-angle glaucoma and ocular hypertension was both safe and effective.

A Hospital Based Study Regarding Awareness of Association Between Glycosylated Haemoglobin and Severity of Diabetic Retinopathy in Type 2 Diabetic Individuals.

INTRODUCTION: Diabetic retinopathy is one of the most common microvascular complications seen in diabetic patients after a long term of uncontrolled glycaemic status as assessed by glycosylated Haemoglobin A (HbA1c). Hence awareness of glycaemic control is necessary to prevent vision threatening complications. AIM: To assess the awareness regarding association between glycosylated Haemoglobin (HbA1c) and diabetic retinopathy among diabetic patients and to assess the impact of lack of this knowledge on the severity of diabetic retinopathy (DR). MATERIALS AND METHODS: This hospital based cross-sectional study was conducted in the ophthalmology OPD on 200 adult diabetic patients, between November 2012 and January 2013, who were assessed for their knowledge regarding association between HbA1c and its impact on the progress of DR. The study was done with the help of a semi structured questionnaire which included demographic details, literacy levels, diabetic status and awareness of HbA1c. STATISTICS USED: Cochran Armitage test for trend, Fisher Exact test, chi-square for trend and Student's t test. RESULTS: Among the 200 diabetic individuals attending our OPD, 180 (90%) were aware of the importance of blood sugar levels and its fluctuation in type 2 diabetes. Only 23 (11.5%) were aware of HbA1c whereas 10 (5%) misinterpreted it as levels of haemoglobin, 3 (1.5%) did not completely comprehend. About 164 (82%) patients were not aware of the significance or the terminology of HbA1c. Out of the 200 patients, 58 patients showed presence of some grade of DR. Amongst these 58 patients, 7(12.1%) were aware of HbA1c and all the11 patients with clinically significant macular oedema (CSME) were aware of the risk factors of elevated blood sugar levels but ignorant of HbA1c. Among the remaining 142 individuals who showed no signs of DR, 16 (27.5%) were aware of and comprehended the role of HbA1c. CONCLUSION: Our study highlights the gross ignorance of role of HbA1c in the progress of DR among diabetic individuals. It is a known fact that the risk of DR reduces by 35% for every 1% reduction in HbA1c. Hence a strict control of blood sugar level with regular monitoring of HbA1c can help diabetic individuals in prevention of progress of DR, thus preventing severe vision loss.