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Biomedical subjects

M J Welch

Publications and source records attributed to M J Welch.

At least 127 records · Page 7Linked to original sources
PubMed1994

Metabolism of receptor targeted 111In-DTPA-glycoproteins: identification of 111In-DTPA-epsilon-lysine as the primary metabolic and excretory product.

The hepatic and renal retention of indium-111 (111In) from 111In-labeled polypeptides has been the subject of many investigations. Because the lysosome is a common intracellular destination for the degradation of polypeptides, we studied the lysosomal metabolism of 111In-DTPA-labeled glycoproteins targeted to cell surface receptors in vitro and in vivo. We found that 111In-DTPA-glycoproteins were degraded to 111In-DTPA-epsilon-lysine, which was slowly released from cells and recovered intact in urine and feces. These results suggest a mechanism for 111In retention at target and non-target sites.

Animals↗
PubMed1994

Inhaled steroids and severe viral infections.

In summary, the blanket inclusion of inhaled corticosteroids in the recent FDA label warning of an association between severe varicella infection and corticosteroid therapy without reference to dosage, and proof of immunosuppression and subsequent increased risk, dose not appear warranted. To date, no link has been established between inhaled steroids and pulmonary or systemic infections. Certainly, with the recent trend of use of higher doses of inhaled corticosteroids, a potential association is possible, but so far, this is only theoretical. Since inhaled corticosteroids have become the recommended drug of choice for many patients with asthma of varying disease severity, according to new recommendations from the National Heart Lung and Blood Institute (38), it is imperative that a sound basis of proof be provided to support this labeling change. It must be realized that this new warning may lead to adverse consequences resulting from the withholding by the patient or physician of a valuable mode of therapy for fear of adverse effects to the patient. Avoidance of inhaled steroid usage, in turn, could result in overuse of other medication that has more definite and frequent deleterious effects than the theoretical risks associated with inhaled steroids. Given the above information and arguments, a number of constructive recommendations about how to proceed at this time can be proposed.

Administration, Inhalation↗
PubMed1994

Effect of RG 12525, a new leukotriene antagonist, on pulmonary function of asthmatic adults.

RG 12525 is a new oral leukotriene D4 (LTD4) antagonist with proven activity in animal and human models of leukotriene-induced bronchoconstriction. In this randomized, double-blind, parallel-group, placebo-controlled study the bronchodilator effects of single oral doses of RG 12525 of 25 and 200 mg or placebo were evaluated in 62 adult asthmatic patients. All patients had previously demonstrated 20% reversibility of FEV1 with an inhaled beta-agonist. They had an unmedicated FEV1 less than 80% of predicted value at the time of the study. Bronchodilator activity was assessed by spirometry before and at multiple time points after dosing for eight hours. A single 200-mg dose of RG 12525 of mg resulted in statistically significantly greater increases in mean maximum change above baseline for FEV1 and FEF25-75% than placebo. The peak effect was observed four to five hours after dosing. The RG 12525 dose of 25 mg dose induced better bronchodilation than placebo but the differences were not significant. Adverse clinical experiences or laboratory abnormalities were not noted.

Adolescent↗
PubMed1993

16 beta-([18F]fluoro)estrogens: systematic investigation of a new series of fluorine-18-labeled estrogens as potential imaging agents for estrogen-receptor-positive breast tumors.

In order to understand the structural features that might lead to an estrogen receptor (ER) based breast tumor imaging agent with improved uptake characteristics, we have synthesized several new analogs of 16 beta-fluoroestradiol (beta FES) and studied their tissue distribution in immature rats. The compounds we prepared were 11 beta-methoxy-beta FES (7a), 11 beta-ethyl-beta FES (7b), 17 alpha-ethynyl-beta FES (8c), 17 alpha-ethynyl-11 beta-methoxy-beta FES (8a), and 11 beta-ethyl-17 alpha-ethynyl-beta FES (8b). All of the analogs exhibit good affinity for ER, ranging at 25 degrees C from 10 to 460, with estradiol equal to 100. Measurement of their octanol/water partition coefficients by an HPLC method allowed us to estimate their level of nonspecific binding and thereby to predict their binding selectivity indices (BSI, i.e., the ratio of their ER-specific to nonspecific binding); the BSI values of three fluorine-substituted analogs exceed that of estradiol. These ligands have been labeled in the 16 beta position with fluorine-18 by the nucleophilic displacement of an alpha-disposed trifluoromethanesulfonate by [18F]fluoride ion. Reduction with lithium aluminum hydride produced the estradiol series ([18F]-7a-c), while treatment with lithium trimethylsilylacetylide afforded the ethynylated series ([18F]-8a-c). The synthesis time was 85 min for [18F]-7a-c and 120 min for [18F]-8a-c, with radiochemical yields ranging from 16 to 43%, and effective specific activities being 90-2900 Ci/mmol (3.3-107 TBq/mmol). In tissue distribution studies in immature female rats, all of the labeled analogs demonstrated ER-selective uptake in the principal target tissues, the uterus and the ovaries, and also in organs with lower titers of ER, the secondary target sites kidney, thymus, fat, and muscle. Although factors other than specific and nonspecific binding obviously affect the tissue distribution of these 16 beta-fluoroestrogens, we find that their ER-specific uptake by both the principal and the secondary target tissues correlates with their BSI values at a high level of statistical significance in most cases. The ethynylated-11 beta-methoxy analog [18F]-8a had high selectivity (uterus to blood ratio) after 3 h and exhibited the highest uterine uptake (percent injected dose/gram) of any fluorine-substituted estradiol ligand we have studied to date. This compound has been chosen for more detailed studies (to be described elsewhere), including clinical trials in human patients diagnosed with primary breast cancer.

Animals↗
PubMed1993

Fluorine-18-labeled progestin ketals: synthesis and target tissue uptake selectivity of potential imaging agents for receptor-positive breast tumors.

We have studied two new fluorine-substituted progestins as potential imaging agents for progesterone-receptor-positive human breast tumors. The steroids are 16 alpha, 17 alpha-fluoroacetophenone ketals of 16 alpha, 17 alpha-dihydroxyprogesterone and 16 alpha, 17 alpha, 21-trihydroxy-19-norprogesterone. Synthesis of the latter compound in seven steps from 19-norandrost-4-ene-3,17-dione is reported. Both compounds demonstrate high affinity for the progesterone receptor (PgR) (52.5 and 240%, respectively, relative to R5020 = 100). The syntheses were adapted to 18F-labeling with 4'-[18F]-fluoroacetophenone, prepared from 4'-nitroacetophenone by nucleophilic substitution with K18F/Kryptofix. Considerable adjustment of reaction conditions was required to effect ketalization using tracer quantities of the ketone. In tissue distribution studies in estrogen-primed immature female rats, both ketals showed selective uterine uptake, which was blocked by coinjection of a saturating dose of the unlabeled progestin ORG 2058. Additionally, metabolic stability of the radiolabel was indicated by the low radioactivity levels seen in bone. Both compounds showed relatively high uptake in fat, in accord with their relative lipophilicities demonstrated by HPLC-derived octanol-water partition coefficients. The selective uterine uptake and metabolic stability of these compounds suggests that this class of PgR ligands might be promising for the selective imaging of receptor-positive tumors if derivatives of reduced lipophilicity can be prepared.

Adipose Tissue↗
PubMed1993

16 beta-[18F]fluoromoxestrol: a potent, metabolically stable positron emission tomography imaging agent for estrogen receptor positive human breast tumors.

16 beta-[18F]Fluoromoxestrol (beta FMOX, 1) is a highly selective, metabolically stable estrogen with potential as a receptor imaging agent. It demonstrates receptor-mediated uptake in the immature rat in the estrogen receptor-rich primary target tissues, uterus and ovaries, as well as, in receptor-poor secondary target tissues, muscle, thymus and kidneys; uptake in the uterus is nearly four times that of the clinically useful 16 alpha-[18F]fluoroestradiol (FES), most likely due to the extended lifetime of the labeled beta FMOX in the blood afforded by its relatively slow metabolism. In vivo and in vitro studies demonstrate a nearly four-fold decrease in metabolism rate between beta FMOX and FES. Dosimetry studies indicate radiation absorbed doses comparable to FES. beta FMOX possesses desirable imaging characteristics and may prove to be a clinically useful imaging agent.

Animals↗
PubMed1993

A synthesis of 7 alpha-substituted estradiols: synthesis and biological evaluation of a 7 alpha-pentyl-substituted BODIPY fluorescent conjugate and a fluorine-18-labeled 7 alpha-pentylestradiol analog.

In an effort to assist in the preparation of ligands for the study of the estrogen receptor (ER), we have developed a new synthesis of 7 alpha-substituted estradiols. The key step in the synthesis involves a copper-catalyzed, alpha-selective, 1,6-conjugate addition of 4-pentenyl magnesium bromide to a suitably protected 6-dehydrotestosterone derivative. Desaturation and then reductive aromatization of the resulting 7 alpha-pentenyl androgen gave the 7 alpha-pentenylestradiol in good yields. The alpha-stereoselectivity of this addition in the testosterone series, compared with the 19-nortestosterone series, is significantly improved by the presence of the C-19 methyl group, which shields the beta face from attack. A key intermediate was functionalized further by substitution with fluorine-18 to provide a potential imaging agent for positron emission tomography, and by conjugation with a BODIPY (Molecular Probes Inc., Eugene, OR, USA) fluorophore to make a fluorescent probe for the estrogen receptor. The synthesis and biological evaluation of these analogs is presented, as well as a discussion of the improvements in the synthetic procedure.

Boron Compounds↗
PubMed1993

Interlaboratory comparison studies on the analysis of hair for drugs of abuse.

Eleven laboratories interested in the analysis of human hair for drugs of abuse participated in a study to determine how well drugs could be detected and quantified in hair. For the two exercises completed to date, substances to be determined were limited to cocaine, benzoylecgonine, and morphine. Samples sent to the participating laboratories included hair from drug users, drug-free hair, and hair into which drugs had been soaked. For the first exercise, the hair samples were sent as powders; for the second, they were in the form of short segments. Results from these studies have shown that the laboratories, with a few exceptions, have performed very well qualitatively. However, scatter in quantitative results was high. Various approaches were used to liberate drugs from the hair, with the most commonly used, acid extractions and enzyme digestions, producing similar results. Laboratories using GC/MS generally performed well and reported no false positives. In contrast, one laboratory analyzing hair directly using MS/MS without extractions produced three of the four false positives and the worst quantitative results.

Cocaine↗
PubMed1993

Improved synthesis of 1-[11C]D-glucose.

An improved synthesis of 1-[11C]D-glucose is described. The major improvement is achieved when a 0.033 M borate buffer at pH 8.1 is used to effect the condensation of d-arabinose with NH4(11)CN. Subsequent reduction of the 1-[11C]D-aldonitriles gives the epimeric sugars 1-[11C]D-glucose and 1-[11C]D-mannose in a ratio of 1.8 +/- 0.57 as the major products. The decay corrected radiochemical yield is about 30% for the mixture of sugars. The overall synthesis, starting with the production of NH4(11)CN, is conducted in a dedicated remote system. The remote gantry was easy to build with commercially available valves and glassware, and has been practically trouble-free after more than 2 years of use. Improved purification and quality control of the final product uses ion chromatography and a more efficient resin, and is also described. A preliminary PET study on a macaque has been conducted using 1-[11C]D-glucose obtained with this new improved synthesis.

Animals↗
PubMed1993

Automated production of oxygen-15 labeled butanol for PET measurement of regional cerebral blood flow.

Because [15O]butanol is the radiopharmaceutical of choice for PET studies of cerebral perfusion and neurological activation, we have developed a microprocessor-controlled radiosynthetic system for the preparation of this radiotracer in up to ten batches at a time. An IBM-compatible minicomputer was programmed to direct the reaction of molecular [15O]oxygen with tri-(n-butyl)borane bound to alumina, followed by purification of product [15O]butanol via solid phase extraction with C18 Sep-Paks and sterile filtration. Routine batch yields of over 150 mCi were achieved with a preparation turn-around time of 6.0 min. The final product had high radiochemical purity, low chemical impurity, and was sterile and apyrogenic. This radiopharmaceutical production system is reliable and suitable for tracer production in clinical PET imaging centers.

Butanols↗
PubMed1993

Application of microwave heating to the synthesis of [18F]fluoromisonidazole.

A modified synthesis of [18F]fluoromisonidazole is reported which makes use of microwave heating to reduce the synthesis time to ca 70 min from EOB. A remote system for column purification, concentration and delivery to an HPLC syringe, which reduces the total absorbed dose to the operator, is also described.

Heating↗
PubMed1993

Evaluation of copper-labeled bifunctional chelate-albumin conjugates for blood pool imaging.

62Cu(T1/2 = 9.8 min) is a generator-produced positron-emitting radionuclide with a half-life amenable to blood-pool imaging with PET. Three bifunctional chelates [cyclic anhydride of diethylenetriaminepentaacetic acid (cDTPAA), 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N ',N", N"'-tetraacetic acid (BAT), and p-carboxyethylphenylglyoxal-bis-(4N-methyl-thiosemicarbazone (CE-DTS)] were conjugated to HSA and labeled with 67Cu. The labeling efficiency of 67Cu-DTS-HSA was > 90%, whereas the labeling yields of 67Cu-DTPA-HSA and 67Cu-benzyl-TETA-HSA were less than 70%. Blood clearance and biodistribution of these three 67Cu-labeled conjugates were determined in rats. Of the three 67Cu-labeled bifunctional chelate-HSA conjugates, 67Cu-benzyl-TETA-HSA remained in the blood pool the longest, achieving stable blood levels at times longer than 24 h post-injection. The 67Cu radioactivity cleared the blood within 60 min post-injection of 67Cu-DTS-HSA, and within 10 min after administration of 67Cu-DTPA-HSA, indicating the dissociation of Cu2+ from these conjugates. Copper-labeled DTS-HSA achieved stable blood concentrations for at least 30 min post-injection and was therefore evaluated as a vascular imaging agent. DTS-HSA and benzyl-TETA-HSA were labeled with 62Cu and administered to a dog for blood-pool imaging using PET. Images were nearly identical to an image taken after administration of C15O. Because of the high labeling efficiency, DTS-HSA can be labeled with 62Cu without purification, making it more practical than 62Cu-benzyl-TETA-HSA as a blood-pool imaging agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Synthesis, radiolabeling and tissue distribution of 11 beta-fluoroalkyl- and 11 beta-fluoroalkoxy-substituted estrogens: target tissue uptake selectivity and defluorination of a homologous series of fluorine-18-labeled estrogens.

We have synthesized six estrogens substituted at the 11 beta-position with a fluoroalkyl or fluoroalkoxy substituent. These compounds bind to the estrogen receptor with moderate to high affinity, with the fluoroalkyl analogs being higher affinity binders than the fluoroalkoxy ones. All of these fluorine-substituted estrogens were prepared in fluorine-18-labeled form, with high radiochemical purity and at effective specific activities (15.4-50.4 TBq/mmol; 415-1362 Ci/mmol) adequate for biodistribution studies. In immature female rats, five of the six fluoroestrogens showed selective uptake by the uterus, with uterine uptake as a percent of the injected dose per gram being 4-9% at 1 h, and uterus-to-blood or uterus-to-muscle ratios being 10-40. Selective uterine uptake was eliminated by co-administration of a blocking dose of unlabeled estradiol. The only compound that did not show selective uterine uptake was 11 beta-fluoropropoxyl estradiol; its rapid metabolism and its low affinity for the estrogen receptor, particularly at 25 degrees C, may account for its lack of specific uptake. The level of bone activity, an index of metabolic defluorination, shows that the defluorination rates of these six estrogens are a complex function of structure and functionality. Least prone to defluorination is 11 beta-(2-fluoroethoxy)estradiol and most prone is 11 beta-(2-fluoroethyl)estradiol. The extent of defluorination of the remaining compounds shows weak evidence for the protective effect of a heteroatom-substituted beta to the site of metabolism (the CH bonds on the fluorine-bearing carbon atom). The binding affinity, tissue distribution and metabolism of these 11 beta-fluoroalkyl- and fluoroalkoxy-substituted estrogens further our understanding of the behavior of fluorine-18-labeled estrogens as potential imaging agents for estrogen receptor-positive breast cancer.

Animals↗
PubMed1993

Metabolism in vitro of radioiodinated N-isopropyl-p-iodoamphetamine by isolated hepatocytes.

An in vitro technique for the determination of radiopharmaceutical metabolism has been developed using isolated hepatocytes. Radioiodinated N-isopropyl-p-iodoamphetamine (IMP; iofetamine, USP) was employed a model tracer in these studies because its labeled metabolites are well-characterized. Hepatocytes isolated from the rat and human produced labeled metabolites in vitro for up to 4 h in a manner similar to that reported for humans in vivo. Identical metabolites were generated by all cell types investigated, but the rate of metabolism differed (rat >> human; female > male; fresh > frozen). The utility of this methodology for the preclinical evaluation of potential radiopharmaceuticals is described.

Adult↗
PubMed1993

Titration of the in vivo uptake of 16 alpha-[18F]fluoroestradiol by target tissues in the rat: competition by tamoxifen, and implications for quantitating estrogen receptors in vivo and the use of animal models in receptor-binding radiopharmaceutical development.

We have measured in vivo the uptake of 16 alpha-[18F]estradiol (FES) by target tissues in the immature rat at increasing dose levels (obtained by dilution of [18F]FES with unlabeled estradiol). This was done to examine the binding capacity of target tissues in vivo and to determine whether the uptake in receptor-rich tissues was flow limited, as this has implications concerning the appropriateness of using receptor-rich tissues in experimental animals as models for FES uptake by receptor-poor breast tumors in humans. We also wanted to establish the dose level of the anti-estrogen tamoxifen required to block target tissue uptake of FES. We found that in untreated rats, specific uptake in the uterus saturated at c. 180 pmol/g, in the ovary at c. 54 pmol/g and in the muscle at c. 2 pmol/g. At an intermediate dose of tamoxifen (570 micrograms/kg), uptake saturated at somewhat lower levels, and at a high tamoxifen dose (1710 micrograms/kg), yet lower specific uptake was evident. In the FES titrations at low dose levels of FES, both the uterus and the ovaries, but not the muscle, showed characteristics of flow-limited uptake, i.e. the uptake-to-dose ratio reached a maximum level. This flow limitation suggests that only when receptor levels are sufficiently low will the FES uptake be related to receptor concentration. While receptor-rich tissues such as the rat uterus will show this flow limitation, the receptor concentration in most primary and metastatic human breast tumors is sufficiently low, so that the uptake should parallel receptor content. In in vivo distribution studies, target tissues (or tumors) with low receptor content will be more fully saturated and ligand more readily displaced. Also, uptake by secondary target tissues (i.e. those with a lower content of estrogen receptor, such as muscle, thymus and kidney) may be better models for assessing the effectiveness of new breast tumor imaging agents than uptake by receptor-rich tissues.

Animals↗
PubMed1993

Quantification of regional myocardial perfusion with generator-produced 62Cu-PTSM and positron emission tomography.

BACKGROUND: Noninvasive assessment of regional myocardial perfusion at rest and after stress is important for the objective evaluation of the effects of coronary artery disease and its response to therapy. Centers that do not have cyclotrons rely on generator-produced radioisotopes for assessment of regional myocardial perfusion with positron emission tomography (PET). The aim of the present study was to develop and implement an approach to quantify regional myocardial perfusion using copper(II) pyruvaldehyde bis-(N4-thiosemicarbazone) (PTSM) labeled with the generator-produced, positron-emitting radionuclide 62Cu (t1/2 = 9.7 minutes). METHODS AND RESULTS: Regional perfusion was estimated from dynamic PET scans after intravenous administration of 62Cu-PTSM in 21 studies in 13 intact dogs evaluated over a wide range of myocardial flow values. In 15 interventions in nine dogs, regional perfusion was also estimated with H2(15)O. Regional perfusion with 62Cu-PTSM was estimated from dynamic blood and tissue time-activity curves, along with the model parameter k1 (forward rate of transport) and the PET parameter FBM (fraction of blood pool activity observed in tissue), using a two-compartment kinetic model. Arterial blood activity was corrected for red blood cell-associated 62Cu. In 44 comparisons, estimates of regional perfusion with 62Cu-PTSM correlated well with estimates obtained with concomitantly administered radiolabeled microspheres (y = 0.90x +/- 0.15, r = 0.95, p < 0.05) over a flow range from 0.23 to 6.14 ml/g per minute. In five healthy human volunteers evaluated at rest with H2(15)O and 62Cu-PTSM, regional perfusion estimated with 62Cu-PTSM was not significantly different from that obtained with H2(15)O (1.05 +/- 0.36 versus 0.96 +/- 0.28 ml/g per minute). 62Cu-PTSM provided high-quality images of the heart. CONCLUSIONS: The results of this study demonstrate that quantification of regional myocardial perfusion is feasible using generator-produced 62Cu-PTSM. Since 62Cu-PTSM can be used to estimate perfusion in the brain, kidney, and tumors as well as in the heart, it is an attractive tracer for centers that rely on generator-produced tracers for the evaluation of perfusion with PET.

Animals↗