Browsing by Subject "drug development"
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Item Analyzing the Scientific Debate of Coxibs and The Ethics Impact of Vioxx's Withdrawal on Drug Regulation and an Ongoing Phase III Clinical Trial with a New Cox-2 Inhibitor(2005-11-01) Fu, Jingwei; Gwirtz, Patricia A.; Rubin, Bernard R.; Jiminez-Williams, CynthiaOn September 30, 2004, Merck & Co. Inc announced voluntary withdrawal of its $25 billion blockbuster drug Vioxx from the market, five and a half years after Voixx received FDA approval. This is the largest prescription drug withdrawal in history. Merck made the decision based on the results of APPROVe (Adenomaous Polyp Prevention on Vioxx) clinical trial, which showed that Voixx had an increased risk of myocardial infarction and cerebral vascular stoke compared with placebo. The repercussions of Merck’s action were tremendous from both a financial aspect and an ethical aspect. The recalling of Vioxx has become an important public health issue and has placed drug regulation agencies in controversy. In April, 2005, Pfizer agreed to voluntarily suspend sales and marketing of its COX-2 inhibitor, Bextra in the United States as requested by the FDA. Vioxx and Bextra withdrawal has left a huge impact on the pharmaceutical industry. Debates are ongoing in the scientific community regarding the use of Cox-2 inhibitors and have caused much confusion in the medical community and in those who use these drugs for pain control for osteo- and rheumatoid arthritis disease. The goal of this report is to analyze the impact of Vioxx withdrawal and comment on how to apply this incident in guiding the industry with regards to drug development, drug regulation, and clinical practice in order to ensure the effectiveness in the drug development and safe usage of new pharmaceutical agents.Item Improving Brain Delivery of TRH: A Novel Prodrug Approach(2018-08-01) De La Cruz, Daniel L.; Prokai-Tatrai, Katalin; Prokai, Laszlo; Lacko, Andras G.The goal of my research project was to validate a novel prodrug design concept for the brain-enhanced delivery of an important neuropeptide, thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2). TRH has a variety of clinically relevant central effects that cannot be utilized with the direct administration of TRH, due to intrinsic characteristics that give rise to metabolic instability and insufficient transport through the blood-brain barrier (BBB). Consequently, large doses are required to generate central effects, which concomitantly induces unwanted hormonal liabilities in the periphery. To overcome these caveats, the prodrug design described herein proposes a novel brain-targeting approach that synergistically utilizes two enzymes, both preferentially expressed in the brain, for the enhanced brain-delivery of TRH. The conjugation of a lipoamino acid (LAA) transport moiety to the N-terminus of a TRH progenitor sequence (Gln-His-Pro-NH2) via a prolyl oligopeptidase (POP)-sensitive linker allows the POP enzyme to release the TRH progenitor sequence at the site-of-action upon crossing the BBB, where it is further transformed by glutaminyl cyclase (QC). QC catalyzes Gln to form pGlu at the N-terminus of the progenitor sequence, thereby releasing TRH. I tested the hypothesis that a representative molecule, developed according to this prodrug design approach, would exhibit adequate drug-likeness for BBB penetration and efficacious release of TRH within the brain. Immobilized artificial membrane chromatography was used to predict the BBB penetration of this experimental prodrug, labeled “PRODRUG 1,” in addition to its calculated logP. Next, PRODRUG (1) was compared to TRH (the “parent” peptide) in an in vitro metabolic stability assessment, followed by an in vivo neuro-pharmacodynamical evaluation in rodents. The Porsolt swim test, PST, an established animal behavioral model that detects depressive-like behavior was used to confirm brain-delivery of prodrug-derived TRH after systemic administration of the prototype prodrug. Capitalizing on TRH’s antidepressant-like effect, the PST results were also used to validate the tail suspension test (TST), a new technique that I implemented in our laboratory for the evaluation of neuroactive compounds with potential antidepressant-like activity. My findings support the extension of the TRH progenitor sequence from the N-terminus, through the conjugation of two LAA residues (each with a 10-carbon sidechain) via a single proline POP-sensitive linker, as a successful means to increase penetration across the BBB and sufficiently bind with cleaving and activating enzymes, POP and QC, respectively, for efficacious TRH release in the brain. Lastly, molecular modeling was used to create a library of similarly designed prodrugs to computationally assess their bindings with POP, the cleaving enzyme, to further explore the customizable prodrug design concept described here. Ultimately, this adaptable prodrug delivery model demonstrates the effectiveness of increased lipophilicity and site-of-action targeting to facilitate brain-enhanced delivery of TRH.Item Mitochondria and Neurodegenerative Diseases: A New Hotspot(Aging and Disease, 2023-05-10) Li, Ang; Cao, Shuqin; Jin, Kunlin; Su, HuanxingGrowing evidence suggests that the prevalence of neurodegenerative diseases (NDs) is on the rise with the aged population with substantially overlapping clinical and pathological features. The journal "Aging & Disease" portals are always responsive to publishing cutting-edge research on age-related neurodegeneration. Even though outstanding progress has recently been made in understanding NDs, the underlying mechanisms involved in neuronal degeneration are yet to be deciphered and addressed. There is credible evidence showing multiple links between mitochondria and NDs, gradually becoming the hotspot in mechanistic or drug development research. The editorial aims to reflect on and discuss some interesting and unique results from the papers published in "Aging & Disease" during the past three years (2020 - 2022).