![]() ![]() We found that each of these receptors play a role in mediating TMJ growth and in mediating TMJ remodeling. There are 2 main estrogen receptors: alpha and beta. In our lab we focused on the role of estrogen and estrogen receptor signaling in mediating TMJ growth and mechanical loading induced remodeling. ![]() However, the biological reason behind this sexual dimorphism is unknown. TMJ diseases predominantly afflict women. The significance of this finding is that manipulating alveolar bone density may be a novel method to prevent relapse. We found that orthodontic tooth movement caused a decrease in alveolar bone density and that relapse returned the bone density back to basal levels. In order to accomplish this, we have examined the effect of orthodontic tooth movement and relapse on mandibular alveolar bone density. Research in our lab is focused on trying to understand the biological differences between these two types of tooth movement, with the goal of determining a method to orthodontically move teeth into a stable position without the use of lifelong retention. However, after the removal of orthodontic appliances, teeth tend to want to go back to their original position. These studies support the interpretation of toxicology studies, help characterize the disposition of givosiran in humans, and support the clinical use of givosiran for the treatment of acute hepatic porphyria.Ĭopyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.For years, orthodontists have been able to move teeth in a predictable fashion. Subcutaneous administration results in adequate exposure of givosiran to the target organ (liver). Givosiran shows similar pharmacokinetics and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. SIGNIFICANCE STATEMENT: Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Thus, givosiran has a low potential of mediating drug-drug interactions involving P450 isozymes and drug transporters. Givosiran is not a substrate, inhibitor, or inducer of P450 isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Renal and fecal excretion were minor routes of elimination of givosiran as approximately 10% and 16% of the dose was recovered intact in excreta of rats and monkeys, respectively. Givosiran metabolized to form one primary active metabolite with the loss of one nucleotide from the 3' end of antisense strand, AS(N-1)3' givosiran, which was equipotent to givosiran. Givosiran was metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species with no human unique metabolites. Givosiran predominantly distributed to the liver by asialoglycoprotein receptor-mediated uptake, and the t 1/2 in the liver was significantly longer (∼1 week). Plasma protein binding was concentration dependent across all species tested and was around 90% at clinically relevant concentration in human. Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. ![]() Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t 1/2 less than 4 hours). Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran is an N-acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. ![]()
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