Phase I, Randomized, Controlled, Third-party Double-blind, Dose Escalating Study of Protexia Administered Intramuscularly at One or Two Time Points in Healthy Human Volunteers

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of Protexia, an experimental drug being developed to protect soldiers against the effects of nerve agents.
Volunteers will be entered into one of five groups. Four of the groups will receive a single intramuscular dose of Protexia or saline placebo on Study Day 1 and will participate in the study for approximately 71 days. One of the groups will receive two intramuscular doses of Protexia or saline placebo - one dose on Study Day 1 and the second dose on Study Day 72. This group will participate in the study for approximately 142 days.
All volunteers will remain at the study site as an inpatient for three days after they are dosed and will be monitored closely by the study doctors and staff. After that, volunteers will return to the study site as outpatients at predetermined intervals. Groups 1, 2, 4, 5 will have a total of 6 follow-up visits and Group 3 will have a total of 12 follow-up visits.
It is expected that this study will provide important information on the safety and tolerabiity of Protexia at one and two doses.

开始日期2008-09-01

申办/合作机构

PharmAthene, Inc.

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100 项与人丁酰胆碱酯酶(Altimmune, Inc.) 相关的转化医学

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项与人丁酰胆碱酯酶(Altimmune, Inc.) 相关的文献（医药）

2023-05-11·Journal of medicinal chemistry1区 · 医学

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer's Disease Mouse Model.

1区 · 医学

Article

作者: Hofmann, Julian ; Stove, Christophe P. ; Steinmueller, Sophie A. M. ; Carles, Allison ; Morilleau, Axelle ; Decker, Michael ; Maurice, Tangui ; Monti, Barbara ; Deventer, Marie H. ; Tutov, Anna ; Poeta, Eleonora ; Spatz, Philipp

We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB₂R) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a β-arrestin 2 (βarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier penetration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of Aβ_25-35-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short- and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB₂R activation in vivo.

2021-02-04·ChemMedChem

Evaluation of Water‐Soluble Mannich Base Prodrugs of 2,3,4,5‐Tetrahydroazepino[4,3‐b]indol‐1(6H)‐one as Multitarget‐Directed Agents for Alzheimer's Disease

Article

作者: Altomare, Cosimo D. ; Nevskaya, Alisa A. ; Voskressensky, Leonid G. ; Purgatorio, Rosa ; Rullo, Mariagrazia ; Catto, Marco ; de Candia, Modesto ; Pisani, Leonardo ; Denora, Nunzio ; Carrieri, Antonio

AbstractDifferent Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6‐phenethyl‐2,3,4,5‐tetrahydroazepino[4,3‐b]indol‐1(6H)‐one (1), a human butyrylcholinesterase inhibitor (hBChE, IC5013 nM) and protective agent in NMDA‐induced neurotoxicity, in in vivo assays. The N‐(4‐methylpiperazin‐1‐yl)methyl derivative 2 c showed a 50‐fold increase in solubility in pH 7.4‐buffered solution, high stability in serum and (half‐life >24 h) and rapid (<3 min) conversion to 1 at acidic pH. Although less active than 1, 2 c retained moderate hBChE inhibition (IC50=3.35 μM) and a significant protective effect against NMDA‐induced neurotoxicity at 0.1 μM. Moreover, 2 c resulted a weaker serum albumin binder than 1, could pass the blood–brain barrier, and exerted negligible cytotoxicity on HepG2 cells. These findings suggest that 2 c could be a water‐soluble prodrug candidate of 1 for oral administration or a slow‐release injectable derivative in in vivoAlzheimer's disease models.

2020-10-01·Biotechnology and Bioengineering2区 · 工程技术

Technoeconomic analysis of semicontinuous bioreactor production of biopharmaceuticals in transgenic rice cell suspension cultures

2区 · 工程技术

Article

作者: Corbin, Jasmine M. ; McDonald, Karen A. ; McNulty, Matthew J. ; Nandi, Somen ; Macharoen, Kantharakorn

AbstractBiopharmaceutical protein production using transgenic plant cell bioreactor processes offers advantages over microbial and mammalian cell culture platforms in its ability to produce complex biologics with simple chemically defined media and reduced biosafety concerns. A disadvantage of plant cells from a traditional batch bioprocessing perspective is their slow growth rate which has motivated us to develop semicontinuous and/or perfusion processes. Although the economic benefits of plant cell culture bioprocesses are often mentioned in the literature, to our knowledge no rigorous technoeconomic models or analyses have been published. Here we present technoeconomic models in SuperPro Designer® for the large‐scale production of recombinant butyrylcholinesterase (BChE), a prophylactic/therapeutic bioscavenger against organophosphate nerve agent poisoning, in inducible transgenic rice cell suspension cultures. The base facility designed to produce 25 kg BChE per year utilizing two‐stage semicontinuous bioreactor operation manufactures a single 400 mg dose of BChE for $263. Semicontinuous operation scenarios result in 4–11% reduction over traditional two‐stage batch operation scenarios. In addition to providing a simulation tool that will be useful to the plant‐made pharmaceutical community, the model also provides a computational framework that can be used for other semicontinuous or batch bioreactor‐based processes.

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