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J A Clanton

Publications and source records attributed to J A Clanton.

At least 19 recordsLinked to original sources
PubMed1995

Noninvasive measures of radiolabeled dextran transport in in situ rabbit lung.

UNLABELLED: Dextrans are nontoxic and can be obtained in a wide variety of molecular weights. The purpose of this study was to label 6-kDa and 40-kDa dextrans with gamma- (99mTc) and positron- (18F) emitting radioisotopes and monitor their transport across the pulmonary microvascular barrier. METHODS: External scan measurements for radiolabeled uncharged dextrans, albumin and red blood cells were obtained in eight blood-perfused in situ rabbit lung preparations. After 3 hr of external scanning, the lungs were removed for postmortem and extravascular distribution volume calculations. Extravascular distribution volumes were obtained in six additional rabbits following 4 hr of dextran perfusion to compare the effect of time. The normalized slope index (NSI), a measure of transvascular transport rate, was calculated for each diffusible tracer. RESULTS: The mean NSI for albumin (0.001676 +/- 0.000537 min-1) was significantly lower than NSI for the 40-kDa dextran (0.002303 +/- 0.0005426 min-1) as well as the 6-kDa dextran (0.004312 +/- 0.001134 min-1). The difference between the 6-kDa and the 40-kDa dextrans was also significant. After 4 hr of equilibration, distribution volumes were not significantly different than those obtained at 3 hr. CONCLUSION: Dextrans can be radiolabeled with gamma and positron emitters and small dextrans traverse the lung microvascular barrier more rapidly than albumin. Our results suggest that the use of small dextrans rather than albumin can reduce scan times in clinical applications and minimize motion artifact associated with the noninvasive gamma detection method.

Animals↗
PubMed1995

Dosimetry of iodine-123-epidepride: a dopamine D2 receptor ligand.

UNLABELLED: Substituted benzamides have been shown to have very high affinity and specificity for the dopamine D2 receptor. One of these is radiolabeled epidepride, an iodine-substituted benzamide currently under evaluation as a SPECT imaging agent. Detailed estimates of the radiation absorbed dose to 26 organs and the whole body from [123I]epidepride have been calculated. METHODS: The dosimetry calculations use a combination of in vivo uptake and biodistribution data from one rhesus monkey and seven humans to estimate residence times in eight organs. The computer program MIRDOSE2 was used to calculate the dosimetry. RESULTS: Results indicate that 75% of the radioactivity is cleared through the urinary tract while the remaining radioactivity clears through the gallbladder and intestinal tract. The radiation absorbed dose can be minimized by administering a high lipid content meal 1.5 hr postinjection to empty the gallbladder and by giving large volumes of fluids throughout the study to induce increased urinary output. CONCLUSION: By emptying the gallbladder and urinary bladder, the lower large intestine becomes the critical organ, 0.102 mGy/MBq (0.38 rad/mCi) followed by the upper large intestine, 0.092 mGy/MBq (0.34 rad/mCi). The effective dose equivalent is 0.025 mSv/MBq (0.092 rem/mCi).

Animals↗
PubMed1993

Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride.

The regional distribution of striatal and extrastriatal dopamine D2 receptors in human brain was studied in vitro with (S)-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-[125I]iodo-2,3-dimethoxybenzamide, [125I]epidepride, using post mortem brain specimens from six subjects. Scatchard analysis of the saturation equilibrium binding in twenty-three regions of post mortem brain revealed highest levels of binding in the caudate (16.5 pmol/g tissue) and putamen (16.6 pmol/g tissue) with lower levels seen in the globus pallidus (7.0 pmol/g tissue), nucleus accumbens (7.2 pmol/g tissue), hypothalamus (1.8 pmol/g tissue), pituitary (1.3 pmol/g tissue), substantia innominata (1.0 pmol/g tissue), and amygdala (0.87 pmol/g tissue). Of note was the presence of dopamine D2 receptors in the four thalamic nuclei studied, i.e. anterior nucleus (1.0 pmol/g tissue), dorsomedial nucleus (0.96 pmol/g tissue), ventral nuclei (0.72 pmol/g tissue), and pulvinar (0.86 pmol/g tissue), at levels comparable to the amygdala (0.87 pmol/g tissue) and considerably higher than levels seen in anterior cingulate (0.26 pmol/g tissue) or anterior hippocampus (0.36 pmol/g tissue). The frontal cortex had very low levels of dopamine D2 receptors (0.17-0.20 pmol/g tissue) while the inferior and medial temporal cortex had relatively higher levels (0.31-0.46 pmol/g tissue). Inhibition of [125I]epidepride binding by a variety of neurotransmitter ligands to striatal, ventral thalamic and inferior temporal cortical homogenates demonstrated that [125I]epidepride binding was potently inhibited only by dopamine D2 ligands. The present study demonstrates that dopamine D2 receptors are present in basal ganglia, many limbic regions, cortex and in the thalamus. The density of thalamic D2 receptors is comparable to many limbic regions and is considerably higher than in cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1993

High affinity dopamine D2 receptor radioligands. 3. [123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain.

Studies of [123I]epidepride uptake in rhesus monkey brain were performed using single photon tomography. Striatal uptake peaked at 0.85% of administered dose/g at 107 min post-injection, then declined slowly to 0.70% of administered dose/g at 6 h. Striatal:posterior brain ratios rose from 2 at 25 min to 6.8 at 105 min, to 15 at 4 h and to 58 at 6.4 h. [123I]Epidepride was displaced by haloperidol (0.1 and 1 mg/kg) with a half-life of washout of 55 min. Little displacement of [123I]epidepride was observed following administration of 1 or 2 mg/kg d-amphetamine, respectively, indicating [123I]epidepride is not easily displaced by endogenous dopamine. In vitro equilibrium binding studies using rat striatum revealed a KD of 46 pM and Bmax of 33 pmol/g tissue at 37 degrees C, while at 25 degrees C the KD was 25 pM and the Bmax 32 pmol/g tissue. In vitro kinetic analysis of association and dissociation curves revealed a half-life for receptor dissociation at 37 degrees C of 15 min and 79-90 min at 25 degrees C. Allowing for the temperature difference, there is good correspondence between in vivo and in vitro dissociation kinetics at 25 degrees C. Increasing in vitro incubation temperature from 25 to 37 degrees C caused a 6-fold increase in the dissociation rate, suggesting that there is a change in binding kinetics at the dopamine D2 receptor at 37 degrees C compared to in vivo binding. The results of this study indicate that [123I]epidepride is an excellent radioligand for SPECT studies of the dopamine D2 receptor in man.

Amphetamine↗
PubMed1993

The bacterial endotoxin test in the PET facility.

A method by which the gel-clot Limulus amebocyte lysate test may be performed in 20 rather than 60 min with sufficient sensitivity to satisfy the needs of the nuclear medicine or positron emission tomography laboratories has been developed and validated for use as a substitute for the Bacterial Endotoxin Test described in the United States Pharmacopeia, 22nd revision. Using this method, results may be obtained from the test prior to the human administration of radiopharmaceuticals without extensive loss of activity and with increased safety when compared to tests performed after administration. Additionally, studies on the shelf-lives of the reagents used in the test were conducted. When refrigerated between use, control standard endotoxin dilutions of 5 EU/ml or greater may be used for at least 1 mo after preparation and reconstituted lysate retains its labeled sensitivity for at least 10 days, considerably longer than the manufacturer's stated shelf-lives.

Ammonia↗
PubMed1992

Visualization of extrastriatal dopamine D2 receptors in the human brain.

[123I]Epidepride, a potent and selective dopamine D2 radioligand, was administered to a 27 year old normal male volunteer. Single photon tomography revealed that peak striatal uptake occurred at 4 h after injection with a striatal:cerebellar ratio of 7.8 rising to over 100 at 18 h post injection. Uptake above the levels seen in cerebellum was also noted in the thalamus, pituitary, hypothalamus and temporal lobe, particularly medially. Single photon tomography with [123I]epidepride allows visualization of extrastriatal dopamine D2 receptors in man.

Adult↗
PubMed1991

High affinity dopamine D2 receptor radioligands. 2. [125I]epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors.

Epidepride, (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenzamide+ ++, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25 degrees C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2. Scatchard analysis of in vitro binding to striatal, medial frontal cortical, hippocampal and cerebellar membranes revealed a KD of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91-1.00 in all four regions. The IC50's for inhibition of [125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 microM to greater than 10 microM. Partial displacement of [125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to alpha 2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent KD of 9 nM. At an epidepride concentration equal to the KD for the D2 receptor, i.e. 25 pM, no striatal alpha 2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the alpha 2 site. Correlation of inhibition of [3H]spiperone and [125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site. In vitro autoradiography revealed high densities of receptor binding in layers V and VI of prefrontal and cingulate cortices as well as in striatum. In vivo rat brain uptake revealed a hippocampal:cerebellar and frontal cortical:cerebellar ratio of 2.2:1 which fell to 1.1:1 following haloperidol pretreatment. These properties suggest that [125I]epidepride is a superior radioligand for the in vitro and in vivo study of striatal and extrastriatal dopamine D2 receptors.

Animals↗
PubMed1991

High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides.

Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "Iodopride" (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, "iclopride" (KD 0.23 nM) and "itopride" (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

Animals↗
PubMed1989

Measurement of lung fluid volumes and albumin exclusion in sheep.

A radioactive tracer technique was used to determine interstitial diethylenetriaminepentaacetic acid (DTPA) and albumin distribution volume in sheep lungs. 125I- and/or 131I-labeled albumin were injected intravenously and allowed to equilibrate for 24 h. 99mTc-labeled DTPA and 51Cr-labeled erythrocytes were injected and allowed to equilibrate (2 h and 15 min, respectively) before a lethal dose of thiamylal sodium. Two biopsies (1-3 g) were taken from each lung and the remaining tissue was homogenized for wet-to-dry lung weight and volume calculations. Estimates of distribution volumes from whole lung homogenized samples were statistically smaller than biopsy samples for extravascular water, interstitial 99mTc-DTPA, and interstitial albumin. The mean fraction of the interstitium (Fe), which excludes albumin, was 0.68 +/- 0.04 for whole lung samples compared with 0.62 +/- 0.03 for biopsy samples. Hematocrit may explain the consistent difference. To make the Fe for biopsy samples match that for homogenized samples, a mean hematocrit, which was 82% of large vessel hematocrit, was required. Excluded volume fraction for exogenous sheep albumin was compared with that of exogenous human albumin in two sheep, and no difference was found at 24 h.

Albumins↗
PubMed1988

(S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[125I]iodo- 2-methoxybenzamide hydrochloride, a new selective radioligand for dopamine D-2 receptors.

From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.

Animals↗
PubMed1987

Magnetic resonance brain tumor imaging in canine glioma.

This study investigates a canine model of experimental brain tumor. Particularly addressed was the usefulness of gadolinium contrast-enhanced MRI for differentiating brain tumor tissue from cerebral edema. Cultured canine glioma cells were injected into the left hemispheres of six adult mongrel dogs. All dogs developed brain tumors. Serum samples drawn prior to and serially after tumor inoculation showed development of antibodies reactive to the tumor. All tumors were visualized with MRI. Contrast-enhanced T1-weighted imaging was the most sensitive with gadolinium producing tumor enhancement due to blood-brain barrier breakdown. Gross and microscopic autopsy findings correlated well with MRIs.

Animals↗
PubMed1986

Bioavailability and penetration of topical amphotericin B in the anterior segment of the rabbit eye.

The penetration of topical amphotericin B was studied in Dutch-belted rabbits using bioassay and radioassay techniques. Seven percent of total amphotericin B in the corneas, as measured by recovered 14-C, and 5% in the aqueous was in a bioactive form. Drug was not detectable by bioassay after single drop administration but after a loading dose approach, drug was present in therapeutic amounts. In inflamed corneas, a pass-through effect was noted with higher levels initially but rapid fall-off subsequently.

Administration, Topical↗
PubMed1986

Corneal penetration of topical amphotericin B and natamycin.

The corneal uptake and penetration of 14C-labelled 0.15% amphotericin B and 5% natamycin were studied in Dutch-belted rabbits. Corneal levels of natamycin were substantially higher than amphotericin B. For both drugs, these levels were influenced by corneal contact time. In corneas debrided of epithelium, both agents entered the corneal stroma and levels were detected in aqueous in the therapeutic range. However, in corneas with intact epithelium, penetration was negligible for amphotericin B (0.23 microgram/gm at 2 mins). By contrast, although penetration of natamycin was greatly reduced, 7.0 micrograms/gm were present at 2 mins.

Administration, Topical↗
PubMed1985

Particulate oral NMR contrast agents.

Insoluble paramagnetic compounds in suspension can be used to achieve visualization of the gastrointestinal system on magnetic resonance imaging (NMR). Particulate preparations of these agents decrease the T1 and T2 of solutions to which they are added. Gadolinium oxalate, a prototype of these particulate agents, was evaluated in vitro and in vivo (in rabbits) by NMR imaging. The effect of this compound upon T1 and T2 in vitro was also quantitated by NMR spectroscopy. Opacification of the upper gastrointestinal tract was achieved with gadolinium oxalate following oral administration. The colon was visualized following rectal administration.

Administration, Oral↗
PubMed1985

111In-labeled eosinophils: localization of inflammatory lesions and parasitic infections in mice.

Based upon recent development of practical isolation techniques for eosinophils, labeling and in vivo imaging of eosinophils has been achieved. Isolation of cells was performed utilizing a Percoll density gradient. The eosinophils were subsequently labeled by a modified 111In-oxine method. Migration of eosinophils in response to intradermal ear-pinna injections of SEA (soluble schistosoma egg antigen), S. mansoni eggs, E. coli, and turpentine was followed with gamma-ray camera imaging from 4 to 48 h. Maximal localization, determined by Gamma 11 data processing, occurred by 4-h post-injection of radiolabel. SEA and S. mansoni eggs provided a greater stimulus for localization than E. coli or turpentine. Neutrophils did not preferentially accumulate. Tissue distribution of labeled eosinophils was greatest in the spleen, followed by liver and bone. 111In-labeled-eosinophil scans are sensitive to parasitic infections, although somewhat nonspecific.

Animals↗
PubMed1985

The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption.

To provide contrast enhancement in magnetic resonance imaging, a new class of compounds has been developed, the paramagnetic metal ion chelates. Gadolinium (Gd) DTPA, a prototype of this class, shows a sufficiently high in vivo stability and low toxicity for use in initial clinical trials. This type of agent, designed for rapid clearance by glomerular filtration, allows the assessment on MRI of renal function, alterations in tissue perfusion, myocardial ischemia, and perhaps most significantly disruption of the blood-brain barrier (BBB). Research at Vanderbilt has demonstrated these applications, with particular emphasis in three areas. Tissue perfusion changes, such as those produced by ligation of the arterial blood supply to portions of the spleen and kidney, cannot easily be detected on unenhanced MRI. These acute tissue infarcts can be readily identified following the administration of Gd DTPA. The question of field strength dependence of Gd DTPA has been addressed by experimentation at 0.15, 0.5, and 1.5 tesla. Furthermore, the ability to detect an alteration of the BBB, when present without associated edema, has been demonstrated with the application of control enhancement. The use of contrast agents in MRI will enhance both the sensitivity and specificity of magnetic resonance imaging.

Animals↗
PubMed1985

Gated magnetic resonance imaging of acute myocardial ischemia in dogs: application of multiecho techniques and contrast enhancement with GD DTPA.

ECG gated magnetic resonance images were obtained in six canines prior to and immediately following occlusion of either the LAD or circumflex coronary artery using a surgically placed snare. Multiecho and single-echo acquisition techniques were utilized 0.25 mmol/kg Gd DTPA was injected as an IV bolus 1 hr following coronary artery ligation. In two animals, the region of ischemic myocardium was clearly visualized on multiecho technique without the use of intravenous contrast. The ischemic zone could be best identified on images with a long TE of 120 msec. Contrast enhancement with Gd DTPA enabled visualization of the ischemic myocardium in all six canines. Administration of Gd DTPA, a perfusion agent, improved both detectability and definition of the myocardial lesions.

Animals↗