Bushra J. Agha

Orally administered DTPA di-ethyl ester for decorporation of 241Am in dogs: Assessment of safety and efficacy in an inhalation-contamination model

Abstract Purpose: Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA)-approved for decorporation of 241Am; however, an oral product is considered more amenable in a mass casualty situation. The di-ethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination. Materials and methods: Single-dose decorporation efficacy of C2E2 administered 24-h post contamination was determined in beagle dogs using a 241Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test. Results: Oral administration of C2E2 significantly increased 241Am elimination over untreated controls and significantly reduced the retention of 241Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic. Conclusions: The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of 241Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies.

Drug Distribution and Biliary Excretion Pattern of a Cyclic Somatostatin Analog: A Comparison of 14C Labeled Drug and a 131I lodinated Drug Analog

A cyclic somatostatin analog was compared to an iodinated analog of the same compound with respect to organ distribution and biliary excretion in the rat. The cyclic hexapeptide was radiolabeled with either 14C or 131I (tyrosine). Organ distribution of the iodinated compound as a function of time was nearly identical to that observed for the non-iodinated compound. Results indicated a rapid uptake by the liver and subsequent rapid excretion of the intact peptide in bile. Activity in other organs examined tended to fall off in a manner similar to the activity in blood with sequential samples. Because of the similarity in the in vivo behavior of the two compounds, the iodinated analog was deemed a suitable model for less invasive distribution studies, and was further examined in the dog using external gamma scintigraphy. In the unanesthetized dog the iodine activity was rapidly taken up by liver and collected in the gallbladder, thus exhibiting a similar rapid excretion pattern to that observed in the rat.

Peptidyl Carbamates as Human Leukocyte Elastase Inhibitors: Design and Synthesis of Desmosine-Like Tetrapeptidyl Carbamate Inhibitors

AbstractThe rational design and synthesis of a series of peptidyl carbamates incorporating a derivatized ornithyl or lysyl residue at the P3 or P4 subsite is described. The derivatized residues were chosen as mimics of desmonsine cross-links ubiquitously found in mature elastin. The alteration of specific residues of the peptidyl carbamate, in addition to the realization of a stereospecific synthesis, required utilization of two convergent synthetic approaches. When tested for inhibitory activity against the serine dependent enzymes, human leukocyte elastase, porcine pancreatic elastase, trypsin, chymotrypsin, as well as acetyl cholinesterase, the compounds were found to be specific inhibitors of the elastases. Thus the series was found to exhibit inhibitor dissociation constants as low as 0.2 × 10−6M and 3.0 × 10−6M for human leukocyte and porcine pancreatic elastase, respectively. Michaelis-Menten kinetics demonstrated active site inhibition. Placement of Nδ-Bz-L-Orn at P4 withp-nitrophenol at P1’(23a) ...