Vaccination of feral pigs (Sus scrofa) using iophenoxic acid as a simulated vaccine.

OBJECTIVES: To develop an encapsulation method for delivery of vaccines to feral pigs, and quantify the effect of iophenoxic acid on captive feral pig blood iodine concentrations to assist in investigation of factors affecting vaccine uptake. DESIGN AND METHODS: Feral pigs were administered iophenoxic acid by oral gavage, and consumption was assessed for different encapsulation methods in baits. Blood iodine concentrations were monitored for eight days after consumption. The relationship between dose rate, time since dosing and blood iodine concentration was assessed for gavaged and baited captive feral pigs. Wild feral pigs were baited with PIGOUT baits containing 20 mg of encapsulated iophenoxic acid to simulate a vaccination program. Using knowledge from the pen studies, bait uptake and factors affecting bait uptake were investigated. RESULTS: Bait-delivered iophenoxic acid led to variable and inconsistent changes in blood iodine concentrations, in contrast to pigs receiving iophenoxic acid by gavage. This precluded accurate assessment of the quantity consumed, but still allowed a conservative determination of bait uptake. Iophenoxic acid in smaller capsules was consumed readily. Increasing baiting intensity appeared to increase bait uptake by wild feral pigs, and pigs of varying sexes, ages and weights appeared equally likely to consume baits. CONCLUSIONS: Encapsulated liquids can be delivered to feral pigs within baits, should the need to vaccinate feral pigs for fertility or disease management arise. High baiting intensities may be required.

Long-lasting systemic bait markers for Eurasian badgers.

This study was carried out to assess whether Rhodamine B, ethyl-iophenoxic acid (EtIPA), and propyl-iophenoxic acid (PrIPA) can be used as long-lasting systemic bait markers for free-living badgers (Meles meles). Between June and November 2003, these chemicals were incorporated into bait distributed around badger setts. Serum, hair, and whiskers from individually marked badgers were collected in the following 4 to 24 wk. Rhodamine B was detectable as fluorescent bands up to 24 wk after ingestion of the bait. Individual badgers were found positive for EtIPA and PrIPA up to 20 wk and 18 wk after exposure, respectively. This study indicates that Rhodamine B, PrIPA, and EtIPA could be used as long-lasting markers for badgers.

Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging.

OBJECT: Convection-enhanced delivery (CED), the delivery and distribution of drugs by the slow bulk movement of fluid in the extracellular space, allows delivery of therapeutic agents to large volumes of the brain at relatively uniform concentrations. This mode of drug delivery offers great potential for the treatment of many neurological disorders, including brain tumors, neurodegenerative diseases, and seizure disorders. An analysis of the treatment efficacy and toxicity of this approach requires confirmation that the infusion is distributed to the targeted region and that the drug concentrations are in the therapeutic range. METHODS: To confirm accurate delivery of therapeutic agents during CED and to monitor the extent of infusion in real time, albumin-linked surrogate tracers that are visible on images obtained using noninvasive techniques (iopanoic acid [IPA] for computerized tomography [CT] and Gd-diethylenetriamine pentaacetic acid for magnetic resonance [MR] imaging) were developed and investigated for their usefulness as surrogate tracers during convective distribution of a macromolecule. The authors infused albumin-linked tracers into the cerebral hemispheres of monkeys and measured the volumes of distribution by using CT and MR imaging. The distribution volumes measured by imaging were compared with tissue volumes measured using quantitative autoradiography with [14C]bovine serum albumin coinfused with the surrogate tracer. For in vivo determination of tracer concentration, the authors examined the correlation between the concentration of the tracer in brain homogenate standards and CT Hounsfield units. They also investigated the long-term effects of the surrogate tracer for CT scanning, IPA-albumin, on animal behavior, the histological characteristics of the tissue, and parenchymal toxicity after cerebral infusion. CONCLUSIONS: Distribution of a macromolecule to clinically significant volumes in the brain is possible using convection. The spatial dimensions of the tissue distribution can be accurately defined in vivo during infusion by using surrogate tracers and conventional imaging techniques, and it is expected that it will be possible to determine local concentrations of surrogate tracers in voxels of tissue in vivo by using CT scanning. Use of imaging surrogate tracers is a practical, safe, and essential tool for establishing treatment volumes during high-flow interstitial microinfusion of the central nervous system.

A surface-modified chylomicron remnant-like emulsion for percutaneous computed tomography lymphography: synthesis and preliminary imaging findings.

RATIONALE AND OBJECTIVES: To assess a surface-modified emulsion as a percutaneous CT lymphographic agent in normal dogs. METHODS: An iodinated chylomicron remnant-like microemulsion was formulated with a mean particle size of 91.3 nm and an iodine concentration of 91 mg I/mL. Contrast material (2 mL) was injected into the subcutaneous tissues of the metatarsus and metacarpus of six normal dogs to enhance popliteal and cervical lymph nodes, respectively. CT images were acquired at 0, 15, 30, 45, 60, 240, 480, and 1440 minutes. RESULTS: Significant lymph node enhancement occurred in as little as 15 minutes after injection and persisted at least 8 hours. Node opacification was most pronounced at 1 to 4 hours postinjection and exceeded 200 HU in some nodes (precontrast attenuation = 45 HU). Marked enhancement of popliteal efferent lymphatics and of iliac and sacral node groups also occurred indicating distribution to second order nodes. Attenuation of enhanced nodes reverted to precontrast levels by 24 hours. CONCLUSION: The new surface-modified, chylomicron remnant-like emulsion provided marked, selective enhancement of targeted lymph nodes after subcutaneous administration. Moreover, the formulation produced significant opacification of more distant node groups from a single injection.

Incorporation of an (125)I-labeled hexa-iodinated diglyceride analog into low-density lipoprotein and high specific uptake by cells of cervical carcinoma cell lines.

The feasibility of using low-density lipoprotein (LDL) to deliver cytotoxic drugs to tumor cells has been explored since the 1980s, when cells of a number of cancer cell lines were found to have higher LDL receptor activity than normal cells. Such differential uptake between tumor and normal cells may provide a unique opportunity to use LDL as a tumor-specific carrier of radiopharmaceuticals for the clinical management of cancer. In this study, an (125)I-labeled hexa-iodinated diglyceride analog, 1, 3-dihydroxypropan-2-one 1,3-diiopanoate (DPIP), was synthesized and incorporated into LDL using a fusion technique. It was found that approximately 500 [(125)I] DPIP molecules were incorporated into each LDL particle. Cells of three human cervical tumor cell lines, HeLa, SiHa and C-33A, were used to examine the cellular uptake of the [(125)I]DPIP-LDL conjugate. It was shown that the [(125)I]DPIP-LDL conjugate was specifically bound to and taken up by cervical tumor cells through an LDL receptor-mediated endocytosis pathway. The results suggest that LDL may be a selective carrier for delivering hydrophobic radiopharmaceuticals to cancer cells and particularly for the diagnosis of cervical tumors.

Diagnostic and therapeutic potential of poly(benzyl L-glutamate).

Poly(benzyl L-glutamate) (PBLG) microcapsules, prepared by a solvent evaporation technique for intravenous injection, are evaluated for their potential use in diagnostic computed tomographic enhancement of liver images. The smaller microcapsules, < 3 microns, loaded with a radiopaque contrast material, ethyl iopanoate (IOPAE), produced prolonged opacification of the liver when delivered intravenously. In vivo tissue distribution studies of PBLG-131I-IOPAE (5 microCi/rat, iv) showed that liver had the highest uptake (percent of injected dose/g of tissue) among other organs 24 h postinjection. An in vitro estrogen receptor assay in pig uteri indicated that PBLG conjugated with estrone did not interfere with estrogen receptor affinity, suggesting the estrogen therapy potential of PBLG-estrone.

The plasma pharmacokinetics of iophenoxic and iopanoic acids in goat.

1. The comparative plasma pharmacokinetics of two organic iodine-containing compounds were evaluated in the goat for their suitability as markers in wildlife studies. 2. After oral administration of a single dose, the plasma elimination half-life for iopanoic acid was considerably more rapid (t1/2 of 1-2 days) than that of iophenoxic acid (t1/2 of 81 days). 3. Similar peak plasma concentrations were obtained after administration of iophenoxic acid (1.5 mg/kg) and iopanoic acid (25 mg/kg); however, the AUC0----infinity for iopanoic acid at doses of 25, 50, and 100 mg/kg were 201 +/- 39, 604 +/- 225, and 1292 +/- 721 (micrograms h/ml +/- SD), respectively, which were less than the value of 36,600 +/- 6387 for the oral administration of iophenoxic acid at 1.5 mg/kg. 4. Iophenoxic acid was chosen as a suitable marker because of its persistence at detectable concentrations in the plasma for 5 months.

Kinetic assessment of apparent facilitation by albumin of cellular uptake of unbound ligands.

Previous studies of the effect of albumin on initial uptake of ligands by isolated cell suspensions or cultures found that the apparent uptake for unbound ligand appeared larger in the presence of binding to the albumin than when albumin was absent. Furthermore, when ligand and albumin were increased in a fixed molar ratio, uptake appeared to be competitively inhibited by the excess albumin. We examined the kinetics underlying this apparent facilitation phenomenon by incorporating unbound fraction of ligand in the medium (fu1) into the general model for diffusion between two compartments. The analysis showed that even in the absence of facilitation by albumin, the apparent rate constant for uptake of unbound ligand (k/fu1) increases as albumin concentration increases but the uptake clearance of unbound ligand remains constant. This theoretical analysis was verified experimentally by measuring the effect of albumin on uptake rates of 14C-taurocholate (12, 24, 48, 60, and 96 microM, with and without 0.87 mM albumin) in a nonphysiological system consisting of two solutions separated by a cellulose membrane. Moreover, when the taurocholate and albumin concentrations were increased in a fixed molar ratio of 0.06 (taurocholate 12-96 microM, albumin 0.2-1.6 mM), the initial uptake rate exhibited the same nonlinear pattern as the previous studies that used living cells. This pattern was due not to saturation of a putative albumin receptor but simply to the concomitant decrease in fu1 which tended to offset the increase in uptake rate due to the increasing total taurocholate concentration. The model was also used to evaluate published data describing the effect of albumin on the uptake of iopanoic acid by cultured hepatocytes. In accordance with the model, k1/fu1 increased as albumin concentration increased, but uptake clearance was independent of albumin concentration. Therefore, the kinetic pattern found in this and other studies with isolated cell suspensions or cultures argues against a special role for albumin in facilitating cellular ligand uptake.

Effect of a change in the luminal perfusion rate on intestinal drug absorption studied by a simple unified organ clearance approach.

A recently proposed simple, noncompartmental, unified organ clearance approach was employed to study the effect of change in luminal perfusion rate (Q) on the steady-state intestinal absorption extraction ratio (E) of drugs. The equation used for correlation or prediction is E = H/(Q + H), where H is the apparent intrinsic intestinal absorption clearance of drug and assumed to be constant under linear conditions. Reported experimental data from intestinal perfusion studies in rats were used to evaluate the applicability or accuracy of the above equation. It was found that the mean difference between the predicted and the reported E values for seven steroids with a very wide range of partition coefficients between n-octanol and water (P) was 4.37% as Q was reduced from 0.497 to 0.247 ml/min. Reported changes in E due to multiple variation in Q (up to about 10 times) for hydrocortisone, progesterone, and iopanoic acid were satisfactorily predicted. The relationship between H and log P and the potential limitation of the present absorption approach are discussed. The present limited study also indicates that the absorption of the steroids with higher lipophilicity is usually less flow dependent.