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Biomedical subjects

R J Callahan

Publications and source records attributed to R J Callahan.

At least 37 records · Page 2Linked to original sources
PubMed1993

Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography.

The distribution of fluconazole in tissue of human volunteers was determined by positron emission tomographic scanning over a 2-h period following the infusion of a tracer dose of 18F-fluconazole (5 to 7 mCi) plus 400 mg of unlabeled drug (the standard daily dose of fluconazole). Previous studies have validated this approach for animals. From serial positron emission tomographic imaging and blood sampling, pharmacokinetics of fluconazole in tissue were determined. There was significant distribution of the radiolabeled drug in all organs studied, with nearly constant levels achieved by 1 h. Plateau concentrations of fluconazole in key organs (micrograms per gram) included the following: whole brain, 4.92 +/- 0.17; heart, 6.98 +/- 0.20; lung, 7.81 +/- 0.46; liver, 12.94 +/- 0.24; spleen, 22.96 +/- 2.5; kidney, 11.23 +/- 0.61; prostate, 8.24 +/- 0.58; and blood, 3.76 +/- 0.30. Since levels of fluconazole of > 6 micrograms/g are needed to treat infection with most strains of Candida and levels of > 10 micrograms/g are needed for Cryptococcus neoformans, Coccidioides immitis, and Histoplasma capsulatum, the following predictions can be made. The current standard dose of 400 mg/day should be more than adequate in the treatment of urinary tract and hepatosplenic candidiasis but problematic in the treatment of candidal osteomyelitis, even with the higher levels that develop after multiple doses. Similarly, higher doses should be considered, particularly in immunocompromised patients, with infection with C. neoformans, H. capsulatum, and C. immitis that involves the central nervous and musculoskeletal systems.

Adult↗
PubMed1993

Metaiodobenzylguanidine: evaluation of its potential as a tracer for monitoring doxorubicin cardiomyopathy.

We evaluated alterations in cardiac adrenergic neuron activity and progression of left ventricular dysfunction in comparison with the severity of structural changes using a rat model of adriamycin cardiomyopathy. Rats were treated with adriamycin (2 mg/kg s.c. once a week) for 6, 7, 8 and 9 wk. Accumulation of 125I-metaiodobenzylguanidine (MIBG) 4 hr after intravenous administration was determined and left ventricular ejection fraction (LVEF) was calculated from gated blood-pool images. H & E and Masson-Trichrome stained specimens of the myocardium were examined by light microscopy. Histopathologic examination demonstrated dose-dependent myocyte damage, although there were no differences between the 8-wk and 9-wk groups. LVEF did not differ between controls and the 6-wk group (81.3% +/- 5.5% versus 82.1% +/- 4.8%, p = ns). LVEF began to decrease slightly in the 7-wk group (75.0% +/- 5.7%, p < 0.05) and showed a remarkable decrease in the 8-wk group (53.7% +/- 2.6%, p < 0.001). In the 9-wk group, LVEF diminished to 47.9% +/- 3.1% (p < 0.001), accompanied by massive pleural effusions and ascites. MIBG accumulation in the heart (%ID/heart) significantly and progressively diminished; 1.42% +/- 0.15% in the 6-wk group, 1.06% +/- 0.16% in the 7-wk group, 0.77% +/- 0.13% in the 8-wk group and 0.34% +/- 0.11% in the 9-wk group, respectively p < 0.001, compared to controls (1.99% +/- 0.30%). These results demonstrate that MIBG accumulation in the heart showed a greater and more linear dose-dependent decrease than LVEF. Furthermore, MIBG uptake was significantly reduced in the 6-wk group where only mild myocyte damage (isolated vacuolation or myofibrillar loss) was observed. Thus, MIBG may be a sensitive biochemical marker of adriamycin cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed1993

Serial course of left ventricular function, perfusion and fatty acid uptake in the cardiomyopathic hamster.

To determine the relationship of metabolic and perfusion changes to alterations in ventricular function in the course of cardiomyopathy, we performed serial measurements of ejection fraction, myocardial perfusion, fatty acid uptake of 3-methyl-p[123I]-phenyl-pentadecanoic acid ([123I]3MPDA) and myocardial histology in Syrian hamsters genetically predisposed to the development of congestive cardiomyopathy (Bio T0-2) (n = 30) and normal age-matched control animals (Bio F1B) (n = 13). To obtain high-resolution information about the myocardium at the time of onset of the first noticeable decrease in ventricular function, a multitracer autoradiographic study using 99mTc-pyrophosphate, 201Tl and [14C]3MPDA was obtained at 90 days of age. Baseline ejection fraction recorded at 60 days averaged 60.3%; by 90 days, it decreased to 54.3% (p < 0.05), falling to 41.3% at 180 days (p < 0.01) and declining to 30% at the end of the study. A progressive increase in the extent of myocytolysis, fibrosis and calcification was seen in the histologic studies as the animals aged. The ratio of fatty acid-to-thallium uptake dropped from 0.51 +/- 0.09 to 0.45 +/- 0.11 (p < 0.01), which is in parallel with the reduction in ejection fraction. The thallium lung-to-heart ratio increased from 0.51 at 90 days to 0.59 at 270 days (p < 0.05), which corresponds to the worsening of cardiac function. The macroautoradiographic studies demonstrated slight uptake of pyrophosphate in the myopathic hamster hearts and minimal changes in the regional distribution of fatty acid compared to that of perfusion. We conclude that the decrease in ventricular function parallels the severity of myocytolysis and fibrosis. Although decreased fatty acid uptake was apparent at an early stage, the extent of the change is modest and is difficult to detect from external images.

Animals↗
PubMed1993

Myocardial substrate utilization and left ventricular function in adriamycin cardiomyopathy.

We evaluated alterations of substrate utilization in a rat model of adriamycin cardiomyopathy with deteriorating left ventricular function. Rats were treated with adriamycin (2 mg/kg), once a week for 6, 8, 9 and 10 wk. Fluorine-18-F-deoxyglucose (18F-FDG) and 125I-beta-methyl-branched fatty acid (125I-BMIPP) were used as tracers of glucose and fatty acid metabolism and 99mTc-hexakis (2-methoxyisobutyl-isonitrile) (99mTc-MIBI) was used as a myocardial blood flow tracer. Left ventricular ejection fraction (LVEF) calculated from gated blood pool images was used as an indicator of cardiac function. LVEF was normal in the 6-wk group (78.0% +/- 4.8%), abruptly decreased in the 8-wk group (43.1% +/- 10.1%) and further deteriorated in the 9-wk group (27.6% +/- 13.4%). Accumulation of 18F-FDG (%kgID/g) in the hearts of adriamycin treated animals progressively decreased compared to controls (2.19% +/- 0.38%); 1.47% +/- 0.42% (p < 0.01) at 6 wk, 1.22% +/- 0.27% (p < 0.001) at 8 wk, 0.69% +/- 0.56% (p < 0.001) at 9 wk and 0.50% +/- 0.08% (p < 0.001) at 10 wk. This decrease occurred earlier than the deterioration in LVEF. Myocardial accumulation of 125I-BMIPP decreased in the advanced stages of adriamycin cardiomyopathy and was well correlated with the decrease in 18F-FDG accumulation. However, the decrease was less profound than for 18F-FDG; 53.7% +/- 9.8% versus 31.6% +/- 25.4% of control at 9 wk (p = NS), 49.5% +/- 15.3% versus 22.6% +/- 3.5% of control at 10 wk (p < 0.05). Accumulation of 99mTc-MIBI did not differ between controls and the adriamycin treated groups. There were no differences in blood glucose levels between controls and adriamycin treatment groups. Both glucose and fatty acid utilization are decreased in adriamycin-induced cardiomyopathy and these critical impairments in energy metabolism are associated with heart failure. Impaired myocardial glucose utilization measured with 18F-FDG may be a particularly sensitive marker of adriamycin cardiomyopathy.

Animals↗
PubMed1992

Pharmacokinetics of 18F-labeled fleroxacin in rabbits with Escherichia coli infections, studied with positron emission tomography.

18F-labeled fleroxacin was used to measure the pharmacokinetics of fleroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mg/kg) was coinjected with the tracer. The pharmacokinetics of [18F]fleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after injection and in groups of rats with Escherichia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measurements. In all three species, there was rapid equilibration of [18F]fleroxacin to significant concentrations in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (greater than 100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (greater than 75 micrograms/g), liver (greater than 50 micrograms/g), blood (greater than 25 micrograms/g), and bone and lung (greater than 10 micrograms/g). Since the MICs for 90% of all Enterobacteriaceae are <2 micrograms/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous system.

Animals↗
PubMed1992

Comparison of technetium-99m-glucarate and thallium-201 for the identification of acute myocardial infarction in rats.

The scintigraphic identification of acute severe ischemic myocardial injury requires a marker that localizes rapidly and specifically in zones of damaged myocardium. Technetium-99m-glucarate, a six-carbon dicarboxylic acid, which behaves in vivo somewhat like fructose, was recently described as a marker of severe acute ischemic injury with necrosis. This study was performed to determine the interval between the onset of myocardial ischemia and initial uptake and the duration of a positive scan in experimental animals. Serial injections and images were recorded over 10 days following ligation of the left anterior descending coronary artery of the rat. The distribution of 99mTc-glucarate was compared to that of regional myocardial perfusion monitored with 201TI. The findings on radionuclide imaging were compared to histologic changes in the myocardium. Sequential pinhole images of both radionuclides were collected at 3 hr, 24 hr, 72 hr and 7-10 days following ligation. Ten rats had normal 201TI distributions, no uptake of glucarate and no evidence of infarction by TTC staining at autopsy. Twenty-one rats had either 201TI lesions or evidence of infarction at autopsy. In 17 of these rats, significant acute 99mTc-glucarate uptake was noted, decreasing at 24 hr, and was not seen at 72 hr or 7-10 days. The extent of perfusion abnormality was greatest at 3 hr in most animals; the lesion decreased in four (33%), increased in one (8%) and remained stable in the remainder. These data suggest that 99mTc-glucarate may be a useful marker of acute myocardial injury.

Animals↗
PubMed1991

Polyclonal human immunoglobulin G labeled with polymeric iron oxide: antibody MR imaging.

Human polyclonal immunoglobulin (Ig) G was attached to a monocrystalline iron oxide nanocompound (MION), a small superparamagnetic probe developed for receptor and antibody magnetic resonance (MR) imaging. The resulting complex, MION-IgG, had a slightly negative surface charge, a molecular weight of 150-180 kDa, and 0.36 microgram of IgG attached per milligram of iron. After intravenous administration of MION-IgG to normal rats, most of the compound localized in liver, spleen, and bone marrow. In an animal model of myositis, MION-IgG caused reduced signal intensity (most apparent on T2-weighted spin-echo and gradient-echo images) at the site of inflammation. No change in signal intensity existed after an injection of unlabeled MION. Site-specific localization of MION-IgG was corroborated with scintigraphic imaging with indium-111 IgG and MION-In-111-IgG and was confirmed histologically with iron staining. These results indicate that antibody MR imaging is feasible in vivo. Target-specific and antibody MR imaging could be easily extended to other applications, including detection of cancer, infarction, and degenerative diseases.

Animals↗
PubMed1991

Cytokine administration alters the distribution of activated lymphocytes to the lung.

The effects of intraperitoneal injections of recombinant interleukin-1 alpha (IL-1; 250,000 U/day), interleukin-2 (IL-2; 50,000 units/day), interferon-gamma (IFN-gamma; 50,000 U/day) and tumor necrosis factor-alpha (TNF; 100,000 U/day), on the biodistribution of concanavalin A (Con A)-activated, indium-111-labeled lymphocytes were evaluated in BALB/c mice. Syngeneic spleen cells were activated for 48 h in medium with Con A (5 micrograms/ml) and maintained in culture for 72 h in IL-2 (1,000 U/ml). Groups of 12 mice were treated for 4 days with either one of the cytokines or saline. On day 4, mice received 10(7) lymphocytes (3-5 mu Ci) intravenously. Mice were sacrificed at 4 and 24 h following injection and the percent of administered dose per organ was determined. TNF and IL-1 produced a significant increase in lung uptake of radiolabeled lymphocytes at 4 and 24 h, whereas IL-2 and IFN-gamma decreased uptake at both time points. IL-1 increased uptake by liver at 4 and 24 h while IL-2 increased uptake only at 4 h. We conclude that the distribution of activated lymphocytes following adoptive transfer is altered by cytokines. This finding may have important implications for cell delivery during adoptive immunotherapy.

Animals↗
PubMed1991

Cardiac blood-pool scintigraphy in rats and hamsters: comparison of five radiopharmaceuticals and three pinhole collimator apertures.

Preclinical evaluation of cardiac drugs may require evaluation of cardiac function in intact animals. To optimize the quality of radionuclide measurements of ventricular function in small animals, a comparison was made of gated blood-pool scans recorded with five blood-pool radiopharmaceuticals (99mTc-labeled human polyclonal IgG, 99mTc-human serum albumin labeled by two methods, and red blood cells radiolabeled with 99mTc via in vivo and in vitro methods) in rats and three pinhole apertures in hamsters. The quality of the radiopharmaceuticals was evaluated by comparing count density ratios (LV/BACKGROUND and LV/LIVER) and ejection fractions recorded with each agent. The edge definition of the left ventricle and count rate performance of the 1-, 2-, and 3-mm apertures was evaluated in hamsters. In general, the images obtained with the radiolabeled cells were superior to those obtained with the labeled proteins and no significant differences between the protein preparations were detected. Left ventricular ejection fractions calculated with all five radiopharmaceuticals were not significantly different. The best quality images were obtained with the 1-mm pinhole collimator. Ejection fraction and acquisition time were inversely related to aperture size. A good compromise between resolution and sensitivity was obtained with the 2-mm pinhole collimator.

Animals↗
PubMed1990

Effect of acute burn trauma on reticuloendothelial system phagocytic activity in rats. II: Comparison of uptake of radiolabelled colloid and bacteria.

The uptake of radiolabelled colloid or bacteria was compared in normal rats and animals subjected to acute burn trauma. The uptake of colloid by the liver was unaffected by burn trauma, but uptake of the labelled bacteria was reduced. Spleen uptake of both colloid and bacteria was reduced by burn trauma while lung uptake was increased. These data are consistent with the hypothesis that acute burn trauma alters reticuloendothelial system phagocytic activity in the rat towards both inert particles and live bacteria.

Acute Disease↗
PubMed1990

Radiolabeling of erythrocytes with technetium-99m: role of band-3 protein in the transport of pertechnetate across the cell membrane.

This study analyzes the transport characteristics of the pertechnetate anion across membranes of human erythrocytes during labeling with technetium-99m (99mTc). Transport of this anion is inhibited after incubation at low temperature, indicating the involvement of a process with high activation energy. Transport is also decreased by two well-known inhibitors of the band-3 anion transport system and is not affected by inhibition of the Na/K/Cl co-transport system. From these results we conclude that, in the process of labeling red blood cells with 99mTc, the pertechnetate anion may reach the interior of the erythrocyte through the band-3 anion transport system.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1990

Localization of Fc and Fab fragments of nonspecific polyclonal IgG at focal sites of inflammation.

Intact IgG, Fc, Fab, and 1/2Fc (reduced and alkylated Fc) were coupled to DTPA, labeled with indium-111 and administered to rats to compare the ability of fragments of IgG to localize at focal sites of inflammation. Two sets of experiments were performed: First, 1, 6, 24, and 48 hr after injection, biodistribution was determined in healthy animals; second, localization at sites of inflammation was determined by scintillation camera imaging of animals with deep-thigh infection due to Escherichia coli. The biodistribution studies demonstrated differences in kidney and liver localization: IgG less than Fc less than Fab less than 1/2Fc (kidney), Fc less than 1/2Fc less than IgG less than Fab (liver). The imaging studies revealed that target-to-background ratio (T/B) and percent residual activity (%RA) for IgG was significantly greater (p less than 0.01) than 1/2 Fc or Fab, and T/B for IgG was greater (p less than 0.01) than Fc. These studies suggest that the Fc portion of IgG is the fragment with the best imaging properties.

Animals↗
PubMed1989

111In-labeled nonspecific immunoglobulin scanning in the detection of focal infection.

We performed radionuclide scanning after the intravenous injection of human IgG labeled with indium-111 in 128 patients with suspected focal sites of inflammation. Localization of 111In-labeled IgG correlated with clinical findings in 51 infected patients (21 with abdominal or pelvic infections, 11 with intravascular infections, 7 with pulmonary infections, and 12 with skeletal infections). Infecting organisms included gram-positive bacteria, gram-negative bacteria, Pneumocystis carinii, Mycoplasma pneumoniae, and Candida albicans. No focal localization of 111In-labeled IgG was observed in 63 patients without infection. There were five false negative results, and nine results were unusable. Serial scans were carried out in eight patients: continued localization correctly predicted relapse in six, and the absence of localization indicated resolution in two. To determine whether 111In-labeled IgG localization was specific for inflammation, we studied 16 patients with cancer. Focal localization occurred in 13 of these patients (5 with melanomas, 5 with gynecologic cancers, and 1 each with lymphoma, prostate cancer, and malignant fibrous histiocytoma). No localization was seen in patients with renal or colon cancer or metastatic medullary carcinoma of the thyroid. We conclude that 111In-labeled IgG imaging is effective for the detection of focal infection and that serial scans may be useful in assessing therapeutic efficacy. This technique may also be helpful in the evaluation of certain cancers.

Abdomen↗
PubMed1989

Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer.

Tumour-infiltrating lymphocytes (TIL) were isolated and expanded from small tumour biopsy samples of twenty-eight patients (thirteen with malignant melanoma, seven with renal cell carcinoma, and eight with non-small-cell lung cancer). The patients were treated with autologous expanded TIL (about 10(10)) and continuous infusions of recombinant human interleukin-2(1-3 x 10(6) U/m2 per 24 h). 29% of the patients with renal cell cancer and 23% of those with melanoma achieved objective tumour responses lasting 3-14 months. Toxic side-effects were limited, and no patient required intensive-care monitoring. Adoptive immunotherapy with TIL and interleukin-2 may be an effective systemic approach to the treatment of some patients with malignant melanoma and renal cell carcinoma.

Carcinoma, Renal Cell↗
PubMed1989

Radiolabeled, nonspecific, polyclonal human immunoglobulin in the detection of focal inflammation by scintigraphy: comparison with gallium-67 citrate and technetium-99m-labeled albumin.

The accumulation of nonspecific polyclonal human immunoglobulin (IgG) radiolabeled with 125I or 111In was compared to that of [67Ga]citrate and [99mTc]albumin in rats with deep thigh inflammation due to Escherichia coli infection. Serial scintigrams were acquired at 1, 3, 24, and in some cases, 48 hr after injection. As early as 3 hr postinjection, [111In]IgG showed greater accumulation at the lesion than [99mTc]HSA (p less than 0.01). Both [125I]IgG and [111In]IgG showed greater accumulation than [67Ga]citrate (p less than 0.01). At 24 hr, IgG image definition increased, while HSA image definition decreased, and the intensity of accumulation of both IgG preparations was greater than that of [67Ga]citrate or [99mTc]HSA (p less than 0.01). At all imaging times, [67Ga]citrate accumulation was surprisingly low. In inflammation produced by Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, Candida albicans, or turpentine, [111In]IgG accumulation was similar to the results obtained with Escherichia coli. These studies suggest that focal sites of inflammation can be detected with radiolabeled nonspecific human polyclonal IgG.

Animals↗
PubMed1989

Utility of the indium 111-labeled human immunoglobulin G scan for the detection of focal vascular graft infection.

The ability to diagnose and localize vascular graft infections has been a major challenge. Recent studies in animal models and humans with focal bacterial infection have shown that radiolabeled, polyclonal, human immunoglobulin G accumulates at the site of inflammation and can serve as the basis for an imaging technique. This study investigated this new technique for the diagnosis and localization of vascular graft infections. Twenty-five patients with suspected vascular infections involving grafts (22), atherosclerotic aneurysms (2), and subclavian vein thrombophlebitis (1) were studied. Gamma camera images of the suspected area were obtained between 5 and 48 hours after intravenous administration of 1.5 to 2.0 mCi (56 to 74 mBq) of indium 111-labeled, human, polyclonal immunoglobulin G. Scan results were interpreted without clinical information about the patient and were subsequently correlated with surgical findings, other imaging modalities, and/or clinical follow-up. In 10 of 10 patients found to have positive scan results, localized infections were confirmed at the involved sites. In 14 of 15 patients whose scan results were interpreted as negative, no vascular infections were identified at follow-up. The patient with false-negative results and recurrent bacteremia from an aortoduodenal fistula was found to have a negative scan outcome at a time when his disease was quiescent. These data suggest that nonspecific, human, indium 111-labeled immunoglobulin G scanning can be a useful noninvasive means of localizing vascular infections.

Adult↗
PubMed1988

Detection of acute inflammation with 111In-labeled nonspecific polyclonal IgG.

The detection of focal sites of inflammation is an integral part of the clinical evaluation of the febrile patient. When anatomically distinct abscesses are present, lesion detection can be accomplished by standard radiographic techniques, particularly in patients with normal anatomy. At the phlegmon stage, however, and in patients who have undergone surgery, these techniques are considerably less effective. While radionuclide methods, such as Gallium-67 (67Ga)-citrate and Indium-111 (111In)-labeled WBCs have been relatively successful for the detection of early inflammation, neither approach is ideal. In the course of studies addressing the use of specific organism-directed antibodies for imaging experimental infections in animals, we observed that nonspecific polyclonal immunoglobulin G (IgG) localized as well as specific antibodies. Preliminary experiments suggested that the Fc portion of IgG is necessary for effective inflammation localization. Since polyclonal IgG in gram quantities has been safely used for therapy in patients with immune deficiency states, we decided to test whether milligram quantities of radiolabeled IgG could image focal sites of inflammation in humans. Thus far, we have studied a series of 84 patients with suspected lesions in the abdomen, pelvis, vascular grafts, lungs, or bones/joints. In 48 of 52 patients with focal lesions detected by surgery, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), the IgG scan correctly localized the site, while 31 patients without focal inflammation had no abnormal focal localization of the radiopharmaceutical. Four patients had false negative scans and one patient had a false positive scan. For this small series, the overall sensitivity and specificity were 92% and 95%, respectively. In this report, we review our experience with this exciting new agent.

Acute Disease↗