Search PubMed⌕ Search

Biomedical subjects

M J Welch

Publications and source records attributed to M J Welch.

At least 163 records · Page 9Linked to original sources
PubMed1991

Antibody fragments labeled with fluorine-18 and gallium-68: in vivo comparison with indium-111 and iodine-125-labeled fragments.

Although monoclonal antibodies have been radiolabeled with many different radionuclides, the application of positron emission tomography (PET) to the imaging of radiolabeled antibodies has been limited to the investigation of a small number of long-lived radionuclides. In this study, we labeled F(ab')2 fragments of a mouse monoclonal antibody (BB5-G1) specific for a human parathyroid surface antigen with the positron emitting radionuclides, gallium-68 and fluorine-18. The biodistribution of the fragments was evaluated in a nude mice model and the results were compared to those obtained with fragments labeled with iodine-125 and indium-111 using conventional labeling techniques. All labeled fragments bound to human parathyroid tissue implanted in nude mice, with parathyroid-to-muscle ratios reaching as high as 10:1, 4 h after administration. A major difference was observed in the uptake and clearance of the various labeled fragments through the kidney. The halogen activity cleared, but the metal radioactivity was retained in the kidney. The results indicate that the fluorine-18 or gallium-68 labeled fragment may be useful for parathyroid imaging with positron emission tomography.

Albumins↗
PubMed1991

Positron labeled muscarinic acetylcholine receptor antagonist: 2- and 4-[18F]fluorodexetimide. Syntheses and biodistribution.

Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-to-cerebellum ratio for 4-FDEX was slightly lower at 1 h (5.9 +/- 0.9) but equally high at 3 h (12.3 +/- 2.0) when compared to 2-FDEX, and there was little bone uptake. The uptake of both 2-FDEX and 4-FDEX into mAChR rich brain regions (e.g. striatum, cortex) was blocked by a dose of dexetimide (5 mg/kg). Our results suggest 4-FDEX is a potential PET agent for study mAChR in vivo.

Acetylcholine↗
PubMed1991

Evaluation of two new bifunctional chelates for radiolabeling a parathyroid-specific monoclonal antibody with In-111.

BB5-G1, a monoclonal antibody specific for human parathyroid cell membrane antigen was conjugated with two new ligands, BrMe2HBED and Br phi HBED and radiolabeled with 111In. We have compared the biodistribution of 111In-labeled BB5 using the new ligands to conventionally labeled (125I-labeled and 111In-DTPA-labeled) BB5 in a nude mouse model. Both 111In-BrMe2HBED-BB5 and 111In-Br phi HBED-BB5 attained high parathyroid-to-blood and parathyroid-to-muscle ratios by 72-96 h. 111In-Br phi HBED-BB5 showed lower %ID/g than 111In-BrMe2HBED-BB5 in the clearance organs, the liver and kidney; renal activity had cleared significantly by 120 h. This work suggests that 111In-Br phi HBED-BB5 offers improved in vitro behavior and may be useful as a radiopharmaceutical for localizing parathyroid tissue.

Animals↗
PubMed1991

TMPHPG: a lipophilic derivative of EHPG for iron, gallium-68 and indium-111 hepatobiliary clearance.

TMPHPG (N,N'-trimethylenebis[2-(2-hydroxy-3,5-dimethylphenyl)glycine]) is a derivative of the ligand EHPG (ethylenebis[2-(o-hydroxyphenyl)glycine]) but is more lipophilic and had been synthesized to increase hepatobiliary clearance. 59Fe(III), 68Ga(III) and 111In(III) complexes of this ligand have been investigated as potential imaging agents for MRI, PET and SPECT, respectively. Metal-dependent differences in blood and liver clearance in mature rats have been evaluated.

Animals↗
PubMed1991

Targeting radiopharmaceuticals--II. Evaluation of new trivalent metal complexes with different overall charges.

Three new multidentate ligands designed to have high affinity for Ga3+, In3+ and Fe3+ have been synthesized. N-(2-hydroxybenzyl)-N'-pyridoxylethylenediamine-N,N'-diacetic acid (HBPLED), N-(2-hydroxy-3,5-dimethylbenzyl)-N'-(3-hydroxy-1,2,5-trimethyl-4- pyridylmethyl)ethylenediamine-N,N'-diacetic acid (Me4HBPLED) and N,N'-bis(3-hydroxy-1,2,5-trimethyl-4-pyridylmethyl) ethylenediamine-N,N'-diacetic acid (DMPLED). These ligands give metal-ligand (M-L) complexes with (M = Ga3+, In3+, Fe3+) overall charges of -1.0 and +1, respectively. The 67Ga, 68Ga and 111In complexes of each of the three ligands and the 59Fe complex of Me4HBPLED were prepared, characterized and their biodistributions determined in rats after intravenous injection. Despite the differences in overall charge, the biological behavior of all three 111In complexes were similar, in that the radioactivity cleared rapidly via the kidney. The biodistributions of the 68Ga and 67Ga complexes were comparable to that of the 111In complex counterpart. Also, the 59Fe-Me4HBPLED biodistribution was not significantly different from those of the 68Ga- and 111In-Me4HBPLED. The renal clearance rate seems insensitive to the overall M-L charge; suggesting that the hydrophilic periphery of the ligand rather than the overall molecular charge determines the biological fate (with respect to renal clearance).

Animals↗
PubMed1991

Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole.

Underlying cellular hypoxia, which may be difficult to detect, has been postulated to be a major cause of morbidity and mortality in sepsis. We employed the novel hypoxic marker [18F]fluoromisonidazole to determine whether cellular hypoxia was present in a peritonitis model of sepsis in the rat. A second group of septic and control rats had organ blood flow measurements determined by the radiolabeled microsphere technique to relate possible ischemia to decreased organ perfusion. No evidence of cellular hypoxia was detected in skeletal muscle, brain, liver, heart, or diaphragm in the septic rats. Ligation of the femoral artery caused a greater reduction in flow (55% decrease vs. 20% decrease, P less than 0.05) and an increased retention of [18F]fluoromisonidazole in skeletal muscle of the septic rats. We conclude that sepsis does not invariably result in systemic, i.e., multiorgan, cellular hypoxia and that underlying cellular hypoxia is not the major pathophysiological abnormality in sepsis. The greater reduction in muscle blood flow and the increased retention of [18F]fluoromisonidazole in the ischemic muscle of septic rats implies that they may be more vulnerable to hypoxia.

Animals↗
PubMed1991

Vocal cord dysfunction in a child with asthma.

Vocal cord dysfunction is uncommon in children. We present the case of a 12-year-old boy with a history of mild, intermittent asthma from 7 to 10 years of age. Subsequently, severe, rapid-onset attacks of respiratory distress occurred with increasing frequency. After a life-threatening attack of airway obstruction with 3 minutes of apnea, he was hospitalized for diagnostic studies. Although pulmonary function tests were normal, laryngoscopy under general anesthesia revealed extremely severe vocal cord spasm induced by minimal contact of the laryngoscope. It required intravenous lidocaine and muscle relaxant to reverse. Spasm was not demonstrable one week later on repeat laryngoscopy and bronchoscopy. No structural abnormalities were seen. There was considerable family stress exacerbated by anxiety about the patient's illness. Parents were told that the condition was different from asthma and probably functional in origin. There have been no further episodes, possibly due to counseling and education in relaxation techniques as well as oral pharmacotherapy for asthma with avoidance of inhaled medications.

Asthma↗
PubMed1991

Comparison of intranasal cromolyn sodium, 4%, and oral terfenadine for allergic rhinitis: symptoms, nasal cytology, nasal ciliary clearance, and rhinomanometry.

Topical intranasal cromolyn sodium, 4% solution, and oral terfenadine, 60 mg tablets, both relieve symptoms of allergic rhinitis with few or no adverse effects, but no comparison of their relative efficacy has been reported. In this double-blind, double-dummy study, 79 patients, ages 12-56 years with symptoms of allergic rhinitis, were randomized to receive either active cromolyn sodium, 1 spray in each nostril QID, or active terfenadine BID along with the appropriate placebo spray or tablet for 4 weeks following a 1-week baseline qualification period. Patients' daily symptom scores were reviewed weekly and constituted the primary efficacy measures. Changes in nasal cytology, nasal ciliary clearance, and rhinomanometry were also assessed. The presence of adverse effects and the overall score of medication efficacy at the end of each week was recorded. The cromolyn sodium and terfenadine groups had comparable baseline scores for severity of allergic rhinitis symptoms and both treatments resulted in significant improvement (P less than .0001) with no statistical difference between them for total symptom scores at the end of 4 weeks. Eosinophils in nasal samples were decreased significantly in the cromolyn treated group with no significant change in the terfenadine-treated group. There were no significant differences between treatment groups in ciliary clearance or rhinomanometry. Adverse effects were uncommon and mild. We conclude that cromolyn sodium and terfenadine are comparably effective and well-accepted treatments for allergic rhinitis.

Administration, Intranasal↗
PubMed1991

New-generation antihistamines.

The Scientific Board of the California Medical Association presents the following inventory of items of progress in allergy and immunology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items of progress in allergy and immunology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items of progress listed below were selected by the Advisory Panel to the Section on Allergy and Immunology of the California Medical Association, and the summaries were prepared under its direction.

Histamine H1 Antagonists↗
PubMed1991

A correlation between muscular strength and hydroxyproline concentration in human patellar tendon.

The connective tissue of the knee is frequently injured by athletes, especially those involved in contact sports. It would be important in the prevention of injury as well as the strategy of physical fitness training to know whether the connective tissue is modified in response to athletic stress or training. The potential modification investigated was variability in the concentration of hydroxyproline, a post-translationally modified imino acid found principally in collagen protein. A correlation was sought between this variability and the leg strength parameters torque (expressed as ft-lbs), torque/body weight and work (expressed as ft-lbs). In a preliminary study of five subjects, no correlation was found between hydroxyproline concentration of the patellar tendon and any of the leg strength parameters. These results suggest that this modification of the collagen in connective tissue does not occur in response to athletic stress or training, but rather, for the small number of subjects investigated, appeared to be relatively constant across a range of leg strengths.

Collagen↗
PubMed1991

Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma.

The positron-emitting estrogenic steroid 16 alpha-[18F]fluoro-17 beta-estradiol (FES) has been shown to exhibit selective uptake in primary breast carcinomas; the uptake of tracer by positron emission tomography (PET) is strongly correlated with the tumor estrogen-receptor concentration. We have now extended the use of this radiopharmaceutical for imaging of metastases of breast carcinoma by PET in 16 patients with clinical or radiographic evidence of metastatic disease. Increased uptake of FES was identified on PET images in 53 of 57 metastatic lesions (93%); only two apparent false-positive foci of FES uptake were seen. In seven of the patients, evaluable PET studies were obtained both before and after initiation of antiestrogen therapy. In all cases, there was a decrease in FES uptake in the tumor deposits after initiation of antiestrogen therapy, and the mean (+/- standard deviation) uptake decreased from 2.22 (+/- 1.23) to 0.80 (+/- 0.42) x 10(3)+ dose/ml. These results indicate that PET with FES has high sensitivity and specificity for detecting metastatic breast carcinoma and provide additional confirmatory evidence that the tumor uptake of this ligand is a receptor-mediated process.

Breast Neoplasms↗
PubMed1991

Assessment of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas.

We have used 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP) for imaging progestin receptors by PET in patients with primary carcinoma of the breast. In vitro binding and in vivo tissue distribution studies in rats have shown that FENP has high specific activity, high affinity for progestin receptors, and receptor-mediated uptake in target tissues. Eight patients with primary breast carcinoma were studied. Breast carcinoma was identified correctly in 50% of the patients with progestin-receptor-positive tumors; however, the FENP uptake was not correlated with progestin-receptor levels. We noted a low target-to-background ratio in humans, with high relative activity in the spine, blood pool, and normal breast tissue. Our findings indicate that FENP is not a suitable agent for imaging progestin receptors in humans.

Breast Neoplasms↗
PubMed1991

Positron-labeled angiotensin-converting enzyme (ACE) inhibitor: fluorine-18-fluorocaptopril. Probing the ACE activity in vivo by positron emission tomography.

To evaluate the feasibility of probing the distribution of angiotensin-converting enzyme (ACE) in vivo using positron emission tomography (PET), 4-cis-[18F]fluorocaptopril (18FCAP) was prepared by the reaction of the triflate 2 with K18F/Kryptofix 222 in MeCN followed by hydrolysis (2 N NaOH). The synthesis time was 1 hr with an average radiochemical yield (EOS) of 12% and a specific activity of greater than 300 Ci/mmol. In vivo biodistribution in rats at 30 min after administration showed high uptakes into organs known to have high ACE concentration (lung, kidney and aorta) and faster clearance of 18FCAP for lung and kidney, compared to the clearance from the aorta. When different amounts of unlabeled 4-cis-fluorocaptopril (SQ 25750) were coinjected in rats, a dose of greater than 5 micrograms/kg decreased the lung uptake by one-half while only 1 microgram/kg decreased the kidney uptake by one-half. In general, the binding in the four tissues studied was saturable with the expected capacity. 18FCAP was administered to a human and displaceable uptake observed in the lung and kidney. The results demonstrate the feasibility of probing ACE in vivo using PET.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Clinical evaluation of triamcinolone acetonide nasal aerosol in children with perennial allergic rhinitis.

Triamcinolone acetonide aerosol (TAA), a topical corticosteroid, now available for intranasal use, has been shown to be highly effective in the treatment of both seasonal and perennial allergic rhinitis (PAR) in adults. To evaluate the efficacy and safety of TAA in children, 210 patients (ages 4 to 12 years) with PAR were randomly assigned to one of three treatment groups (placebo, TAA 82.5 micrograms/day, or TAA 165 micrograms/day). Medication was given tid over 12 weeks in a double-blind fashion. Response to medication was evaluated using symptom scoring, physician evaluation, and, in 44 patients, nasal airflow determinations by anterior rhinomanometry. The higher dose of TAA (165 micrograms/day) significantly improved rhinitis symptoms relative to placebo: the total nasal symptom score and most individual symptom scores (eg, nasal stuffiness, itch, sneezing) were significantly better, duration of rhinitis symptoms (hours per day) was significantly reduced, and nasal airflow in a subset of patients showed significant improvement. The lower dose of TAA (82.5 micrograms/day) was superior to placebo by the same parameters as the higher dose, but this improvement was not as consistently significant as the higher dose. There were no clinically significant adverse events; nasal irritation and epistaxis were rare with a similar incidence among treatment groups. In conclusion, TAA at 165 micrograms/day was effective in controlling the symptoms of PAR and in improving nasal airflow in pediatric patients; the lower dose (82.5 micrograms/day) was marginally effective. Both doses were safe and well-tolerated in the children studied.

Administration, Inhalation↗
PubMed1991

20-[18F]fluoromibolerone, a positron-emitting radiotracer for androgen receptors: synthesis and tissue distribution studies.

To develop an androgen receptor-based, positron-emitting imaging agent for prostate tumors, we have prepared 20-fluoromibolerone (F-Mib) and evaluated its tissue distribution. This compound was synthesized in eight steps from 7 alpha-methyl-19-nortestosterone, with fluorine introduced in the penultimate step by fluoride ion displacement on a spirocyclic sulfate. Fluoromibolerone was obtained in 9%-19% radiochemical yield (decay corrected), at 1.5 hr after bombardment, with an effective specific activity of 217-283 Ci/mmol. The relative binding affinity of F-Mib is 53 (versus R1881 = 100 or mibolerone = 118). In tissue distribution studies in diethylstilbestrol-treated male rats, 18F-Mib demonstrates high target/tissue uptake efficiency and selectivity: the prostate uptake at 0.5 hr and 4 hr is 1.0%-1.3% injected dose/gram tissue (ID/g) and 0.5%-0.6% ID/g, respectively; the prostate-to-blood and the prostate-to-muscle (non-target) ratios are both ca. 4 at 0.5 hr, and increase to ca. 12 by 4 hr after injection. The observed distribution of 18F-Mib suggests that it may be useful for in vivo imaging of prostatic tumors in man by positron emission tomography.

Animals↗
PubMed1991

Metabolic imaging with gallium-68- and indium-111-labeled low-density lipoprotein.

Low-density lipoprotein (LDL) labeled with either gallium-68 (68Ga) or indium-111 (111In) was evaluated as a potential PET or SPECT radiopharmaceutical for determination of hepatic lipoprotein metabolism in rabbits. Gallium-68 or 111In was linked to LDL via diethylenetriaminepentaacetic acid (DTPA) with a 25-70% radiochemical yield. Studies in vivo that compared 68Ga- or 111In-DTPA-LDL with dilactitol-[125I]-tyramine LDL and 131I-LDL showed that both 68Ga- and 111In-labeled LDL behaved as residualizing radiotracers. Localization of radioactivity within the liver of normal rabbits was visualized clearly with [68Ga]DTPA-LDL by PET and with [111In]DTPA-LDL by gamma scintigraphy. Significant differences were observed in hepatic uptake of normal compared with hypercholesterolemic rabbits in which low-capacity LDL receptor-mediated catabolism was saturated. Gallium-68 and 111In-DTPA-LDL are attractive radiopharmaceuticals for noninvasive delineation of tissue LDL metabolism under normal and pathophysiologic conditions.

Animals↗