A Sorbitol Dehydrogenase Inhibitor of Exceptional in Vivo Potency with a Long Duration of Action:  1-(R)-{4-[4-(4,6-Dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl}ethanol

2002 ◽  
Vol 45 (20) ◽  
pp. 4398-4401 ◽  
Author(s):  
Banavara L. Mylari ◽  
Peter J. Oates ◽  
William J. Zembrowski ◽  
David A. Beebe ◽  
Edward L. Conn ◽  
...  
Keyword(s):  
Sorbitol Dehydrogenase ◽  
Duration Of Action ◽  
Long Duration

scholarly journals Measurement of the dynamics of stimulation and inhibition of steroidogenesis in isolated rat adrenal cells by using column perfusion

1974 ◽  
Vol 142 (2) ◽  
pp. 287-294 ◽  
Author(s):  
P. J. Lowry ◽  
Colin McMartin
Keyword(s):  
Cyclic Amp ◽  
Time Course ◽  
Acth Stimulation ◽  
Duration Of Action ◽  
Adrenal Cells ◽  
Small Column ◽  
Long Duration ◽  
Full Effect ◽  
Rapid Fall

Isolated adrenal cells were perfused in a small column by using Bio-Gel polyacrylamide beads as an inert supporting matrix, and the time-course of the response to various stimuli was observed by measuring fluorogenic 11-hydroxycorticosteroids in the effluent. A small but significant response was observed 1 min after stimulation with physiological concentrations of ACTH (adrenocorticotrophin), but the response did not start to build up rapidly for 3–4min and eventually reached a plateau after 9–10min. A similar pattern of events was observed for the decay of the steroid output on removal of ACTH. ACTH analogues, including one with a long duration of action in vivo, were found to produce responses with similar kinetics. However, cyclic AMP caused a more rapid increase in steroidogenesis and its effects were more short-lived after withdrawal. If, as present evidence suggests, cyclic AMP is produced rapidly after ACTH stimulation the delayed build-up of the steroidogenic response to ACTH would indicate that cyclic AMP may not be the intracellular mediator. When inhibitors were applied during ACTH stimulation, aminoglutethimide, which blocks mitochondrial conversion of cholesterol into pregnenolone (3β-hydroxypregn-5-en-20-one), caused a rapid fall in steroid output (1 min), whereas cycloheximide took longer to achieve its full effect. Nevertheless, the response had fallen by 50% in 2 min, indicating a much shorter half-life than that previously reported for the labile protein implicated in steroidogenesis. In addition the rapid response to cyclic AMP makes it unlikely that steroid production is induced as a result of initiation of protein synthesis. This suggests that the labile protein plays an obligatory but permissive role in the development of the response. Column perfusion has proved to be a simple technique which can readily yield accurate data on responses of cells to stimulants and inhibitors.

scholarly journals Phenol sulphotransferase and uridine diphosphate glucuronyltransferase from rat liver in vivo and in vitro. 2,6-Dichloro-4-nitrophenol as selective inhibitor of sulphation

1977 ◽  
Vol 165 (3) ◽  
pp. 553-559 ◽  
Author(s):  
Gerard J. Mulder ◽  
Egbert Scholtens
Keyword(s):  
Rat Liver ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Biological Processes ◽  
Uridine Diphosphate ◽  
Duration Of Action ◽  
Long Duration

Microsomal UDP-glucuronyltransferase and cytosolic sulphotransferase share many substrates, such as phenols and hydroxamic acids. In a search for a selective inhibitor of sulphation, several phenolic compounds were tested. 2,6-Dichloro-4-nitrophenol is introduced as a selective inhibitor of sulphation in vivo, having no effect on UDP-glucuronyltransferase activity. As substrate for both conjugating enzymes the phenolic drug harmol (7-hydroxy-1-methyl-9H-pyrido[3,4-b]indole) was used. In the rat in vivo 2,6-dichloro-4-nitrophenol caused almost complete inhibition of harmol sulphation after a single intraperitoneal injection (26μmol/kg) for 48h; the percentage of harmol sulphated decreased from 75% in controls to 5% in the treated rats. The percentage of harmol glucuronidated increased from 25 to 95%. Pentachlorophenol was equally effective but also highly toxic. Salicylamide had only a very-short-lasting inhibitory effect on sulphation. In vitro, 2,6-dichloro-4-nitrophenol inhibited sulphation of harmol by a rat liver postmitochondrial supernatant completely at 1μm, whereas even at 100μm it had no effect on glucuronidation of harmol. It is concluded that 2,6-dichloro-4-nitrophenol is a selective inhibitor of sulphation and, further, that its long duration of action makes it suitable for studies on the regulatory role of sulphation in some biological processes.

The In Vivo Profile Of AZD3199: A Novel, Fast Acting B2-Agonist With A Long Duration Of Action

2011 ◽  
Author(s):  
Alan Young ◽  
David Nicholls ◽  
Stephen Connolly ◽  
Garry Pairaudeau ◽  
Roger V. Bonnert ◽  
...  
Keyword(s):  
Duration Of Action ◽  
Long Duration ◽  
Fast Acting

scholarly journals The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer

2012 ◽  
Vol 103 (3) ◽  
pp. 522-527 ◽  
Author(s):  
Brent Graham ◽  
Jayne Curry ◽  
Tomoko Smyth ◽  
Lynsey Fazal ◽  
Ruth Feltell ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Small Cell ◽  
Small Cell Lung ◽  
Duration Of Action ◽  
Long Duration

SKY59, A Novel Recycling Antibody for Complement-mediated Diseases

2020 ◽  
Vol 27 (25) ◽  
pp. 4157-4164 ◽  
Author(s):  
Taku Fukuzawa ◽  
Junichi Nezu
Keyword(s):  
Inhibitory Effect ◽  
Biologic Agent ◽  
Microbial Infection ◽  
Duration Of Action ◽  
Complement Activity ◽  
Body Of Knowledge ◽  
Therapeutic Benefits ◽  
Long Duration ◽  
Recycling Technology ◽  
Current Therapies

Background: The complement system usually helps protect against microbial infection, but it could also be involved in the onset of various diseases. Inhibition of complement component 5 (C5) with eculizumab has resulted in a significant reduction of hemolysis, reduction of thromboembolic events, and increased survival in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). However, eculizumab requires frequent intravenous infusions due to the abundance of C5 in plasma and some patients may still experience breakthrough hemolysis. This review introduces the recent body of knowledge on recycling technology and discusses the likely therapeutic benefits of SKY59, a novel recycling antibody, for PNH and complement-mediated disorders. Methods: By using recycling technology, we created a novel anti-C5 antibody, SKY59, capable of binding to C5 pH-dependently. Results: In cynomolgus monkeys, SKY59 robustly inhibited C5 and complement activity for significantly longer than a conventional antibody. SKY59 also showed an inhibitory effect on C5 variant p.Arg885His, whereas eculizumab does not suppress complement activity in patients with this type of mutation. Conclusion: SKY59 is a promising anti-C5 biologic agent that has significant advantages over current therapies such as long duration of action and efficacy against C5 variants.

scholarly journals Mechanisms and Pharmaceutical Action of Lipid Nanoformulation of Natural Bioactive Compounds as Efficient Delivery Systems in the Therapy of Osteoarthritis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1108
Author(s):  
Oana Craciunescu ◽  
Madalina Icriverzi ◽  
Paula Ecaterina Florian ◽  
Anca Roseanu ◽  
Mihaela Trif
Keyword(s):  
Drug Delivery ◽  
Bioactive Compounds ◽  
Targeted Delivery ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Joint Disease ◽  
Duration Of Action ◽  
Immune System Activation

Osteoarthritis (OA) is a degenerative joint disease. An objective of the nanomedicine and drug delivery systems field is to design suitable pharmaceutical nanocarriers with controllable properties for drug delivery and site-specific targeting, in order to achieve greater efficacy and minimal toxicity, compared to the conventional drugs. The aim of this review is to present recent data on natural bioactive compounds with anti-inflammatory properties and efficacy in the treatment of OA, their formulation in lipid nanostructured carriers, mainly liposomes, as controlled release systems and the possibility to be intra-articularly (IA) administered. The literature regarding glycosaminoglycans, proteins, polyphenols and their ability to modify the cell response and mechanisms of action in different models of inflammation are reviewed. The advantages and limits of using lipid nanoformulations as drug delivery systems in OA treatment and the suitable route of administration are also discussed. Liposomes containing glycosaminoglycans presented good biocompatibility, lack of immune system activation, targeted delivery of bioactive compounds to the site of action, protection and efficiency of the encapsulated material, and prolonged duration of action, being highly recommended as controlled delivery systems in OA therapy through IA administration. Lipid nanoformulations of polyphenols were tested both in vivo and in vitro models that mimic OA conditions after IA or other routes of administration, recommending their clinical application.

Further pharmacological evaluation of a novel synthetic peptide bradykinin B2 receptor agonist

2013 ◽  
Vol 394 (3) ◽  
pp. 353-360 ◽  
Author(s):  
Martin Savard ◽  
Julie Labonté ◽  
Céléna Dubuc ◽  
Witold Neugebauer ◽  
Pedro D’Orléans-Juste ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Synthetic Peptide ◽  
Receptor Agonist ◽  
Rabbit Lung ◽  
Hypotensive Action ◽  
Duration Of Action ◽  
Selective Agonist ◽  
Comparable Magnitude

Abstract We recently identified a novel human B2 receptor (B2R) agonist [Hyp3,Thi5,NChg7,Thi8]-bradykinin (NG291) with greater in vitro and in vivo potency and duration of action than natural bradykinin (BK). Here, we further examined its stability and selectivity toward B2R. The hypotensive, antithrombotic, and profibrinolytic functions of NG291 relative to BK and its analogue ([Hyp3,Thi5,(4-Me)Tyr8(ΨCH2NH)Arg9]-BK) (RMP-7) were also tested. Contraction assays using isolated mouse stomachs (containing kinin B1R, B2R, and kininase I- and II-like activities) showed that NG291 is a more potent contractant than BK and is inhibited by HOE-140 (B2R antagonist) but unaffected by R954 (B1R antagonist), whereas both decreased the potency of BK. In stomach tissues from B2R knockout mice, BK maintained its activity via B1R, whereas NG291 had no contractile effect, indicating that it was selective for B2R. Unlike BK, NG291 was not degraded by rabbit lung ACE. Comparing intravenously administered BK and NG291 revealed that NG291 exhibited more potent and prolonged hypotensive action and greater antithrombotic and profibrinolytic activities. These effects were of comparable magnitude to RMP-7 and were absent in B2R knockout mice. We concluded that NG291 is a novel biostable B2R-selective agonist that may prove suitable for investigating the (pre)clinical cardioprotective efficacy of B2R activation.

Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo

1986 ◽  
Vol 29 (10) ◽  
pp. 2088-2093 ◽  
Author(s):  
Suvit Thaisrivongs ◽  
Donald T. Pals ◽  
Douglas W. Harris ◽  
Warren M. Kati ◽  
Steve R. Turner
Keyword(s):  
Renin Inhibitor ◽  
Duration Of Action ◽  
Design And Synthesis ◽  
Prolonged Duration
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