Orally administered penta-ethyl ester prodrug of DTPA for the decorporation of americium-241

Diethylenetriaminepentaacetic acid (DTPA) is an intravenously administered chelating agent that is used to facilitate the elimination of 241Am from contaminated individuals. Despite its long history of use in chelation therapy, its optimal dose has not been clearly established. To evaluate the potential of DTPA to bind 241Am under biological conditions, in vitro binding studies were conducted in rat, beagle, and human plasma. Dose-response curves for DTPA were established, and DTPA was determined to be most efficient in human plasma and least efficient in rat plasma. These results suggest that species differences must be considered when translating the efficacy of DTPA from animals to humans. The oral delivery of DTPA is challenged by its permeability-limited bioavailability, limiting its utility in mass casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester of DTPA was explored. Initial assessments of the prodrug identified favorable physicochemical properties for oral delivery. Consistent with the measured pK?a? values, the prodrug exhibited pH-dependent solubility and lipophilicity of a weak base that is suitable for absorption. Caco-2 permeability assay confirmed the improved epithelial transport of the prodrug over DTPA. From in vitro assessments, the prodrug appeared to be sufficiently stable against premature hydrolysis during gastrointestinal transit. The prodrug was further evaluated in pharmacokinetic, biodistribution, and efficacy studies in rats. A single dose oral administration of the prodrug demonstrated significant absorption over 24 h based on the urinary excretion data. From the urine composition, bioactivation was determined to be extensive but incomplete. Tissue distribution at 12 h was limited primarily to the gastrointestinal tract. A single dose intravenous administration of the prodrug resulted in significant fecal excretion, indicating that biliary clearance is also important to the elimination process. From the pharmacokinetic analysis, the oral administration of the prodrug appeared to be exhibit favorable characteristics for decorporation, including some potential improvements over intravenously administered DTPA. In rats contaminated with 241Am by inhalation, a single dose treatment with the prodrug significantly enhanced decorporation compared to placebo. Overall, DTPA penta-ethyl ester exhibited promising physicochemical, pharmacokinetic, and therapeutic attributes as an orally administered prodrug of DTPA for radionuclide decorporation.Doctor of Philosoph

Species-dependent effective concentration of DTPA in plasma for chelation of 241AmI

Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent that is used to facilitate the elimination of radionuclides, such as americium, from contaminated individuals. Its primary site of action is in the blood, where it competes with various biological ligands, including transferrin and albumin, for the binding of radioactive metals. To evaluate the chelation potential of DTPA under these conditions, the competitive binding of 241Am between DTPA and plasma proteins was studied in rat, beagle and human plasma in vitro. Following incubation of DTPA and 241Am in plasma, the 241Am-bound ligands were fractionated by ultrafiltration and ion-exchange chromatography, and each fraction was assayed for 241Am content by gamma scintillation counting. Dose-response curves of DTPA for 241Am binding were established, and these models were used to calculate the 90% maximal effective concentration, or EC90, of DTPA in each plasma system. The EC90 were determined to be 31.4, 15.9 and 10.0 μM in rat, beagle and human plasma, respectively. These values correspond to plasma concentrations of DTPA that maximize 241Am chelation while minimizing excess DTPA. Based on the pharmacokinetic profile of DTPA in humans, after a standard 30 μmol kg−1 intravenous bolus injection, the plasma concentration of DTPA remains above EC90 for approximately 5.6 h. Likewise, the effective duration of DTPA in rat and beagle were determined to be 0.67 and 1.7 h, respectively. These results suggest that species differences must be considered when translating DTPA efficacy data from animals to humans and offer further insights into improving the current DTPA treatment regimen

Trans-vertebral Regional Cooling for Spinal Cord Protection during Thoracoabdominal Aortic Surgery : An Experimental Study

We developed a simple cooling method for spinal cord protection against ischemic injury during aortic surgery. The neuroprotective effects of our method were investigated using an animal study. Selective spinal hypothermia was produced by means of originally-designed cooling pads placed over the lower thoracic and lumbar vertebral column. Spinal cord ischemia was induced by cross-clamping the thoracic aorta for 60 min in beagle dogs. The neuroprotective effects were evaluated by a multi-modal study. The motor-evoked potentials of the spinal cord resulting from transcranial electric stimulation (MEPs) were recorded during both the ischemic and reperfusion periods. Hindlimb motor function was graded with the Tarlov score, and a histologic examination of the spinal cord injury was performed, at 24 hours after ischemia in animals undergoing hypothermia (hypothermia group: n = 7) or a sham (control group: n = 7). The spinal cord temperatures at the lower thoracic (T10) and lumbar (L3) levels decreased by -9.1°C per hour and -8.1°C per hour, respectively. The amplitude of the MEPs decreased during ischemia in both groups of animals, and significantly recovered during the early phase of aortic reperfusion in the hypothermia group. The Tarlov scores in the hypothermia and control groups were 3.3 ± 1.0 and 1.1 ± 1.5 (mean ± SD, p = 0.015), respectively. Histopathologic study revealed that ischemic injury of the lumbar cord was reduced in the animals undergoing hypothermia. Trans-vertebral regional cooling reduced ischemic spinal cord injury in a canine study. The current method is potentially feasible for clinical use, especially in view of its technical simplicity and few procedure-related complications

Examination of the Effective Utilization of the CARELINK® Remote Monitoring System after its Introduction

AbstractBackground: Japan started using the CARELINK® (Medtronic, Inc, Minneapolis, MN, USA) remote monitoring system in April 2009. However, in some cases, the device failed to transmit a message after registration or according to schedule. We investigated the difference between patients who could make effective use of CARELINK® system and those who could not.Subjects and Method: Sixty patients who had registered until December 2009 at our institution were analyzed. These patients were divided into two groups: those who were able to use the device effectively (group G, n = 49) and those who were not (group F = 11). Patient background, automatic or manual telemetries, new or existing implant patient, presence of adverse events, and the use or non-use of a checklist at the time of introduction were compared between the two groups.Results: In group G, more patients used a checklist at the time of introduction than that in group F (use of checklist/total, 31/49 in group G vs. 3/11 in group F; P, 0.029). No significant difference was observed in other factors between the two groups.Conclusion: We consider that the method used to explain the system are important to make the patients understand handling methods of CARELINK® system. The number of patients introduced to remote monitoring of implantable devices will continue to increase in the future; therefore, we must continue to develop innovative approaches for their effective us

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion.. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone

Preparation of alginate beads containing a prodrug of diethylenetriaminepentaacetic acid

A penta-ethyl ester prodrug of the radionuclide decorporation agent diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was encapsulated in alginate beads by the ionotropic gelation method. An optimal formulation was found by varying initial concentrations of DTPA pentaethyl ester, alginate polymer, Tween 80 surfactant and calcium chloride. All prepared alginate beads were ~1.6 mm in diameter, and the optimal formulation had loading and encapsulation efficiencies of 91.0 ± 1.1 and 72.6 ± 2.2%, respectively, and only 3.2 ± 0.8% water absorption after storage at room temperature in ~80% relative humidity. Moreover, Fourier transform infrared spectroscopy showed that DTPA penta-ethyl ester did not react with excipients during formation of the DTPA penta-ethyl ester-containing alginate beads. Release of prodrug from alginate beads was via anomalous transport, and its stability enhanced by encapsulation. Collectively, these data suggest that this solid dosage form may be suitable for oral administration after radionuclide contamination

Orally Administered DTPA Penta-Ethyl Ester for the Decorporation of Inhaled 241Am

Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [14C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared to a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of 241Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of 241Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized

Nonaqueous Gel for the Transdermal Delivery of a DTPA Penta-ethyl Ester Prodrug

Diethylenetriamine pentaacetic acid penta-ethyl ester, designated as C2E5, was successfully incorporated into a nonaqueous gel for transdermal delivery. The thermal and rheological properties of a formulation containing 40% C2E5, 20% ethyl cellulose, and 40% Miglyol 840® prepared using the solvent evaporation method demonstrated that the gel had acceptable content uniformity and flow properties. In vitro studies showed that C2E5 was steadily released from the gel at a rate suitable for transdermal delivery. Topical application of the gel at a 200 mg C2E5/kg dose level in rats achieved significantly higher plasma exposures of several active metabolites compared with neat C2E5 oil at the same dose level. The results suggest that transdermal delivery of a chelator prodrug is an effective radionuclide decorporation strategy by delivering chelators to the circulation with a pharmacokinetic profile that is more consistent with the biokinetic profile of transuranic elements in contaminated individuals

Electrophysiological Analysis of Chronic Atrial Fibrillation Associated with Mitral Valve Disease by Using Spectral Analysis

Several authors have suggested that periodic activation is related to maintenance of atrial fibrillation (AF). The aim of this study was to examine periodic electrical activations in both atria that may lead to the generation and maintenance of AF associated with valvular diseases by means of fast Fourier transform (FFT) analysis. Atrial electrograms (AEGs) were analyzed in 15 persistent AF patients, who underwent pulmonary vein orifice (PVO) isolation with mitral valve surgery. Intraoperatively, AEGs of 4 seconds duration were acquired at 48 epicardial sites, 24 each from the right and left atrium (RA, LA). Dominant peaks (DPs) examined using FFT were present in 26% of all sampling points (380/1440). Prominent clustering of DPs was mostly observed on the LA. The mean AF cycle length (mAFCL) estimated from DP frequency was significantly shorter in LA than that in RA (178 ± 32 msec vs 24 7 ± 58, p = 0.0003). The shortest AF cycle length in each patient was mainly found in the LA. The PVO isolation procedures successfully eliminated AF in 87% of patients (13/15). In cases of recurred AF (2/15), the difference in mAFCL between bilateral atria was significantly smaller than in the case of successful AF elimination (17 ± 7 msec vs 76 ± 56, p = 0.042). FFT analysis of intraoperative mapping data clarified that periodic activity was present predominantly in LA. It may be possible to predict the efficacy of surgical procedures for eliminating AF using this technique.This work was supported in part by a Grant-inAid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (no. 10470275; to Dr Sueda).The main concepts of this work were presented at the 49th international congress of the European Society for Cardiovascular Surgery, Dresden, Germany, 2000