May « 2017 « New Drug Approvals

10 posts published by DR ANTHONY MELVIN CRASTO Ph.D during May 2017

Synthetic cathinones drug profile - EMCDDA home page

An amphiphilic hydrogel network was synthesized from a cross-linked poly(2-hydroxyethyl methacrylate) backbone copolymerized with the monomers 3-(trimethoxysilyl)propyl methacrylate (PMA) and dimethylaminoethyl methacrylate (DMAEMA) using tetraethylene glycol diacrylate (TEGDA) as cross-linker and using the radical initiator system comprising ,,‘,‘-tetramethylethylenediamine and ammonium peroxydisulfate. The degree of hydration of hydrogel slabs was investigated as functions of varying monomer compositions and cross-link density and as a function of pH and ionic strength of the bathing medium. As much as a 45% increase in hydration was observed for hydrogels containing 15 mol % DMAEMA upon reducing the pH of the bathing medium from 8.0 to 2.0. This confirms the pH-modulated swelling of amine-containing hydrogels. Increasing the concentration of TEGDA cross-linker from 3 to 12 mol % in a 10 mol % DMAEMA-containing hydrogel resulted in only a 10% reduction in the degree of hydration of the gel. There was, however, a 40−50% reduction in the degree of hydration of a 15 mol % DMAEMA hydrogel upon increasing the molar composition of PMA from 0 up to 20 mol %. The presence of PMA confers hydrophobic character that reduces hydration and introduces additional cross-links that reduce network mesh size. The water content of the hydrogel was consistently higher in buffers of lower ionic strength. The reversible pH-dependent swelling observed in these studies, along with the control of cross-link density afforded by the PMA component, endows these biocompatible materials with potential for use in pH-controlled drug delivery of more hydrophobic drugs and present new compositions for in vitro and in vivo biocompatibility studies.

Metformin, The Anti-Aging Miracle Drug - Jeffrey Dach MD

Chapter 3719: CONTROLLED SUBSTANCES

N2 - Tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce the monocytoid differentiation of HL-60 human leukemia cells. The cellular receptor for PMA is protein kinase C. However, cellular events distal to protein kinase C phosphorylation are also critical steps toward differentiation. These events may include specific programs of oncogene transcription that have been associated with phorbol ester-induced leukemic cell differentiation. Recently, it has been found that topoisomerase II could be activated by protein kinase C-mediated serine phosphorylation and that PMA treatment of HL-60 cells enhanced extractable topoisomerase II from these cells. Additionally, topoisomerase II-reactive antineoplastic drugs could block PMA-induced differentiation of HL-60. This enzyme has been implicated in gene regulation, and drug-induced, topoisomerase II-mediated DNA cleavage sites have been identified within cellular oncogenes. Thus, topoisomerase II could play a critical role in the signal transduction cascade leading from PMA-protein kinase interaction to monocytoid differentiation. We have examined this relationship between topoisomerase II and PMA-induced differentiation through measurements of drug-induced, topoisomerase II-mediated DNA cleavage (via alkaline elution) in PMA-treated HL-60 cells. Etoposide-induced DNA cleavage was reduced 10-fold in HL-60 cells treated with 10 nM PMA for 24 h. Neither dimethyl sulfoxide (which produces granulocytoid differentiation) nor non-differentiation-inducing phorbol esters could produce this effect. The decreased cleavage was not due to a PMA-induced inhibition of cell-associated etoposide and was demonstrable in nuclei isolated from PMA-treated cells. The decrease was not simply related to decreased cellular proliferation rate as reflected in the inhibition of DNA synthesis because conditions leading to marked inhibition of DNA synthesis did not necessarily inhibit etoposide-induced DNA cleavage. By contrast, lower concentrations of PMA inhibited etoposide-mediated DNA cleavage disproportionately compared with PMA effects on DNA synthesis. Interestingly, PMA reduced cleavage induced by the topoisomerase II-reactive DNA intercalator 4’-(9-acridinylamino)methanesulfon-m-anisidide by 2-fold, suggesting that specific drug-DNA interactions could partially overcome the PMA-induced effect that resulted in decreased etoposide-induced, topoisomerase II-mediated DNA cleavage. Nuclear proteins in 0.35 M NaCl extracts from untreated or PMA-treated HL-60 cells were virtually identical in topoisomerase II activity and in topoisomerase II-associated drug sensitivity. This suggested that it was PMA-induced changes in cellular chromatin rather than in topoisomerase II itself that resulted in an altered chromatin-drug or chromatin-topoisomerase II interaction. This chromatin structural change, however, could not be demonstrated to have occurred within the c-myc oncogene despite the marked transcriptional down-regulation of c-myc following PMA treatment. However, prior work had suggested that the transcriptional inactivation of this gene may not be accompanied by alterations in chromatin structure. This system is particularly useful in defining whether specific nuclear events, such as altered programs of gene transcription, are mechanistically related to differentiation and whether topoisomerase II may have a role therein.

3719.01 Controlled substances definitions

AB - Tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce the monocytoid differentiation of HL-60 human leukemia cells. The cellular receptor for PMA is protein kinase C. However, cellular events distal to protein kinase C phosphorylation are also critical steps toward differentiation. These events may include specific programs of oncogene transcription that have been associated with phorbol ester-induced leukemic cell differentiation. Recently, it has been found that topoisomerase II could be activated by protein kinase C-mediated serine phosphorylation and that PMA treatment of HL-60 cells enhanced extractable topoisomerase II from these cells. Additionally, topoisomerase II-reactive antineoplastic drugs could block PMA-induced differentiation of HL-60. This enzyme has been implicated in gene regulation, and drug-induced, topoisomerase II-mediated DNA cleavage sites have been identified within cellular oncogenes. Thus, topoisomerase II could play a critical role in the signal transduction cascade leading from PMA-protein kinase interaction to monocytoid differentiation. We have examined this relationship between topoisomerase II and PMA-induced differentiation through measurements of drug-induced, topoisomerase II-mediated DNA cleavage (via alkaline elution) in PMA-treated HL-60 cells. Etoposide-induced DNA cleavage was reduced 10-fold in HL-60 cells treated with 10 nM PMA for 24 h. Neither dimethyl sulfoxide (which produces granulocytoid differentiation) nor non-differentiation-inducing phorbol esters could produce this effect. The decreased cleavage was not due to a PMA-induced inhibition of cell-associated etoposide and was demonstrable in nuclei isolated from PMA-treated cells. The decrease was not simply related to decreased cellular proliferation rate as reflected in the inhibition of DNA synthesis because conditions leading to marked inhibition of DNA synthesis did not necessarily inhibit etoposide-induced DNA cleavage. By contrast, lower concentrations of PMA inhibited etoposide-mediated DNA cleavage disproportionately compared with PMA effects on DNA synthesis. Interestingly, PMA reduced cleavage induced by the topoisomerase II-reactive DNA intercalator 4’-(9-acridinylamino)methanesulfon-m-anisidide by 2-fold, suggesting that specific drug-DNA interactions could partially overcome the PMA-induced effect that resulted in decreased etoposide-induced, topoisomerase II-mediated DNA cleavage. Nuclear proteins in 0.35 M NaCl extracts from untreated or PMA-treated HL-60 cells were virtually identical in topoisomerase II activity and in topoisomerase II-associated drug sensitivity. This suggested that it was PMA-induced changes in cellular chromatin rather than in topoisomerase II itself that resulted in an altered chromatin-drug or chromatin-topoisomerase II interaction. This chromatin structural change, however, could not be demonstrated to have occurred within the c-myc oncogene despite the marked transcriptional down-regulation of c-myc following PMA treatment. However, prior work had suggested that the transcriptional inactivation of this gene may not be accompanied by alterations in chromatin structure. This system is particularly useful in defining whether specific nuclear events, such as altered programs of gene transcription, are mechanistically related to differentiation and whether topoisomerase II may have a role therein.

The aim of this work is to investigate the synthesis of proteoglycans during the cell cycle ..