Accuracy of intra-operative PTH measurement during subtotal parathyroidectomy for tertiary hyperparathyroidism after renal transplantation

Background and aims: Intra-operative parathyroid hormone (IOPTH) results are not known in the setting of tertiary hyperparathyroidism (HPT) after renal transplantation. Materials and methods: A retrospective analysis of 35 tertiary HPT patients who all underwent subtotal parathyroidectomy and IOPTH monitoring was conducted. Results: The mean follow-up time was 2.2±1.4years. Thirty-four patients were cured; one patient (2.8%) had a persistent disease and was cured after reoperation. Median parathyroid hormone (PTH) (median percent decrease from highest) at baseline and at 5, 10, 20, and 30min were 244, 78 (69%), 63 (75%), 53 (79%), and 49pg/ml (83%), respectively. Four patients who were cured had a decrease of 50% at 10min. The sensitivity of the test was 94% at 10min using the Miami criteria. Conclusion: This study shows that IOPTH in tertiary hyperparathyroidism has a high sensitivity. However, because of the low risk of persistent hyperparathyroidism when a subtotal parathyroidectomy is performed, its potential impact on the overall success rate is very small. We therefore do not recommend the routine use of IOPTH in tertiary hyperparathyroidis

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.

Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat

Accuracy of intra-operative PTH measurement during subtotal parathyroidectomy for tertiary hyperparathyroidism after renal transplantation

Intra-operative parathyroid hormone (IOPTH) results are not known in the setting of tertiary hyperparathyroidism (HPT) after renal transplantation

Accelerating the Discovery of Biologically Active Small Molecules Using a High-Throughput Yeast Halo Assay ⊥

The budding yeast Saccharomyces cerevisiae, a powerful model system for the study of basic eukaryotic cell biology, has been used increasingly as a screening tool for the identification of bioactive small molecules. We have developed a novel yeast toxicity screen that is easily automated and compatible with high-throughput screening robotics. The new screen is quantitative and allows inhibitory potencies to be determined, since the diffusion of the sample provides a concentration gradient and a corresponding toxicity halo. The efficacy of this new screen was illustrated by testing materials including 3104 compounds from the NCI libraries, 167 marine sponge crude extracts, and 149 crude marine-derived fungal extracts. There were 46 active compounds among the NCI set. One very active extract was selected for bioactivity-guided fractionation, resulting in the identification of crambescidin 800 as a potent antifungal agent

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds

Backbone N-methylation is common among peptide natural products and has a significant impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was determined by backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (MW = 755) with three N-methyl groups, showed an oral bioavailability of 28% in rat