Biomedical subjects

R J Nickles

Publications and source records attributed to R J Nickles.

At least 37 records · Page 2Linked to original sources

PubMed1998

Fluorine-18-fluoro-L-DOPA dosimetry with carbidopa pretreatment.

UNLABELLED: This article presents dosimetry based on the measurement of fluoro-DOPA activity in major tissues and in the bladder contents in humans after oral pretreatment with 100 mg carbidopa. METHODS: Bladder activity was measured continuously by external probe and calibrated using complete urine collections. Quantitative dynamic PET scans provided time-activity curves for the major organs. Bladder wall dosimetry was calculated using the methods of MIRD Pamphlet No. 14. Effective dose was calculated as described in ICRP Publication 60. RESULTS: Mean absorbed dose to the bladder wall surface per unit administered activity was 0.150 mGy/MBq (0.556 rad/mCi) with the realistic void schedule used in our studies. The dose was 0.027 mGy/MBq (0.101 rad/mCi) to the kidneys, 0.0197 mGy/MBq (0.0728 rad/mCi) to the pancreas, and 0.0186 mGy/MBq (0.0688 rad/mCi) to the uterus. Absorbed doses to other organs were an order of magnitude or more lower than the bladder, 0.009-0.015 mGy/MBq. The effective dose per unit administered activity was 0.0199 mSv/MBq (0.0735 rem/mCi.) CONCLUSION: Urinary excretion of fluoro-DOPA was altered significantly by pretreatment with carbidopa. In general, any manipulation of tracer metabolism in the body should be expected to produce changes in biodistribution and dosimetry. The largest radiation dose was to the bladder wall, for which our estimate was one-fifth of that from the original report. The methods used reflect realistic urinary physiology and typical use of this tracer. The principles of MIRD Pamphlet No. 14 should be used in planning studies using tracers excreted in the urine to minimize the absorbed dose.

Aromatic Amino Acid Decarboxylase Inhibitors↗

PubMed1998

Human biodistribution and dosimetry of the PET perfusion agent copper-62-PTSM.

UNLABELLED: Copper-62-pyruvaldehyde bis(N4-methyl)thiosemicarbazone (PTSM) has been proposed as a generator-produced radiopharmaceutical for perfusion imaging using PET. Several clinical studies have demonstrated the ability of 62Cu-PTSM to quantitate myocardial and cerebral perfusion in humans. Because 62Cu-PTSM is generator-produced, it can be provided to clinical centers without cyclotron availability and, therefore, represents a cost-effective, practical PET perfusion tracer for clinical applications. To assess the safety, time-dependent biodistribution, and whole-body and organ-specific absorbed radiation dose estimates of this tracer, a Phase I study of 62Cu-PTSM was performed using whole-body imaging with PET in 10 healthy volunteers and with the radiopharmaceutical delivered by a compact modular generator unit. METHODS: Five male and five female subjects underwent a series of clinical tests and head-to-midthigh, whole-body PET scans at three time points over 1 hr after intravenous injection of 62Cu-PTSM. Before injection of the tracer, PET transmission scans were performed and used to correct the emission data for attenuation. Final image data were expressed in units of mCi/cc. Using standard organ weights, the percent injected dose per organ was calculated. Biodistribution data were obtained at three different time points and from these data biological half-lives in different organs were determined for calculation of radiation absorbed dose estimates. RESULTS: The liver was seen as the critical organ receiving a dose of 0.0886 rad/mCi. This organ defined the maximum single injected dose at 56 mCi using the limit of 5 rads to a critical organ per study per year. The whole-body dose is 0.0111 rad/mCi, resulting in a 0.622 rad exposure with a maximum single injection dose. Only trace levels of activity were found in the urine, which suggests low levels of urinary excretion and bladder exposure. No significant clinical, electrocardiographic or laboratory abnormalities were seen after the injection of 62Cu-PTSM. CONCLUSION: Copper-62-PTSM is a clinically safe radiopharmaceutical with favorable dosimetry for human studies at injected doses significantly above those projected for use in clinical studies.

Adult↗

PubMed1997

A rather intense source of fast neutrons for small scale activation.

A thick beryllium target has been developed for installation onto a small proton cyclotron (CTI RDS 112), providing an intense source of fast neutrons for activation purposes. Careful attention was paid to cooling and irradiation geometry, allowing cubic centimeter scale samples to approach the proton beam strike surface to within 5 mm. This proximity assures approximately equal to 10(11) neutron/s passing through the irradiated sample when 20 microgramsA of 11 MeV protons are incident on the beryllium primary target.

Beryllium↗

PubMed1997

Evaluation of fluorinated m-tyrosine analogs as PET imaging agents of dopamine nerve terminals: comparison with 6-fluoroDOPA.

UNLABELLED: Fluorinated m-tyrosine analogs were evaluated as PET imaging agents and compared with 6-fluoroDOPA in the visualization of dopamine nerve terminals. METHODS: The three m-tyrosine analogs, 6-[18F]fluoro-L-m-tyrosine (6-FMT), 2-[18F]fluoro-L-m-tyrosine (2-FMT) and 6-[18F]fluoro-fluoromethylene-DL-m-tyrosine (6-F-FMMT), were prepared via electrophilic radiofluorination using [18F]acetylhypofluorite. These three analogs, as well as 6-[18F]fluoro-L-DOPA (6-FD), were injected into sets of rhesus monkeys, and serial PET images were acquired. Plasma samples were collected at different times after tracer administration, and metabolite analyses were done using high-performance liquid chromatography (HPLC). RESULTS: Visual inspection of the PET images obtained using these four tracers showed that the best image contrast was obtained with 6-FMT. Patlak analysis with a reference tissue input function yielded a mean uptake rate constant for 6-FMT of 0.019 min-1, a value twice those for the other tracers including 6-FD. CONCLUSION: These results demonstrate the superiority of 6-[18F]FMT in visualizing dopamine terminals in the rhesus monkey brain and suggest that 6-[18F]FMT is the tracer of choice in the assessment of dopamine metabolism in the living human brain.

Animals↗

PubMed1996

Improving the yield of 2-[18F]fluoro-2-deoxyglucose using a microwave cavity.

We have investigated the use of a microwave cavity (Labwell AB, Sweden) to improve the radiochemical yield of 2-[18F]fluoro-2-deoxyglucose (2-[18F]FDG). After characterizing the heating properties of the cavity, three steps of the Hamacher 2-[18F]FDG synthesis which require heating--azeotropic distillation of the target water, nucleophilic substitution, and hydrolysis of the product--were investigated separately. The average radiochemical yield of 2-[18F]FDG for the microwave synthesis, using the phase transfer reagent tetrabutylammonium bicarbonate, was 62 +/- 4% (72 +/- 5%, decay corrected, synthesis time = 31 min).

Deoxyglucose↗

PubMed1996

The synthesis of fluorine-18 lomefloxacin and its preliminary use in human studies.

Lomefloxacin is a new fluorine-containing antibiotic that has recently been approved for general use. Fluorine-18 lomefloxacin has been prepared by fluoride exchange between fluorine-18 fluoride and lomefloxacin in DMSO. Both time and temperature of the reaction have been optimized and conditions developed for the isolation and purification of the labeled product in a form suitable for oral administration. The exchange reaction provides sufficient labeled material for human studies with pharmacologically relevant quantities of the drug. We have performed preliminary human studies with this compound using positron emission tomography to estimate the tissue distribution of the compound and show the distribution of the compound into the liver and lungs.

Animals↗

PubMed1996

Sherpa brain glucose metabolism and defense adaptations against chronic hypoxia.

The brain of hypoxia-tolerant vertebrates is known to survive extreme oxygen limitation at least in part because of very low rats of ATP utilization and ATP production. To asses whether similar adaptations are involved in healthy humans during hypoxia adaptation over generational time, we initially used positron-emission tomography measurements of glucose metabolic rates in the brain of Quechuas, whose ancestors have been indigenous to the Andes at altitudes between approximately 3,300 and 4,500 m for several hundred years. Workers in this field generally believe that the lineage of Sherpas has been indigenous to the Himalayas for even longer and that Sherpas and other peoples indigenous to the Tibetan plateau are perhaps the most exquisitely hypoxia adapted of all humans. For this reason, in this study we extended our database to include Sherpas. With the use of the same protocol as before, two metabolic states were analyzed: 1) the presumed normal (hypoxia-adapted) state, monitored as soon as possible after subjects left the Himalayas and 2) the deacclimated state, monitored after 3 wk at low altitudes. Positron-emission tomography measurements of 2-[18F]deoxy-2-fluoro-D-glucose metabolic rates, quantified in 26 regions of the brain, indicated that the Sherpas' brain metabolism differed significantly from that of Quechuas but was essentially identical to that of lowlanders. Region-by-region patterns were similar in all three groups, indicating that the regional organization of glucose metabolism in the brain is a conservative, relatively constant characteristic.

Adaptation, Physiological↗

PubMed1995

Myocardial kinetics of a putative hypoxic tissue marker, 99mTc-labeled nitroimidazole (BMS-181321), after regional ischemia and reperfusion.

BACKGROUND: A new nitroimidazole complex, 99mTc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques. METHODS AND RESULTS: To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([14C]palmitate and [3H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15 +/- 11 mumol.h-1.g dry wt-1, mean +/- SEM), systolic wall thickening (20 +/- 6%), and myocardial oxygen consumption (3 +/- 1 mL.min-1.100 g-1) and an increase in exogenous glucose utilization (75 +/- 13 mumol.h-1.g dry wt-1). Systolic wall thickening recovered by only 8 +/- 3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t1/2 = 136 +/- 1 versus 80 +/- 1 minutes, P < .05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia (r = -.68 +/- .05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7 +/- 0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution. CONCLUSIONS: Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.

Animals↗

PubMed1995

Development of an improved target for [18F]F2 production.

An A1 body target with improved yields of electrophilic [18F]F2 on the Siemens/CTI 11 MeV proton cyclotron at Wisconsin has been developed. The saturation yield is 3.10 +/- 0.40 GBq/microA for beam currents up to 45 microA. The target has routinely produced 20-40 GBq of [18F]F2 for clinical and experimental use over 1600 microA-h operation, with a maximum yield to date of 45.5 GBq (1.2 Ci). Target design, performance and reliability are discussed.

Aluminum↗

PubMed1995

Positron emission tomography in drug evaluation: influence of three different catechol-O-methyltransferase inhibitors on metabolism of [NCA] 6-[18F]fluoro-L-dopa in rhesus monkey.

We compared the influence of three different catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on the metabolism of no-carrier-added (NCA) 6-[18F]fluoro-L-dopa (6-FDOPA) in one Rhesus monkey. All three COMT inhibitors improved 6-FDOPA availability in plasma, increased the specific uptake in the brain and thus improved 6-FDOPA uptake measurements using positron emission tomography (PET). Best results were obtained with Ro 40-7592.

Amidines↗

PubMed1995

Enhanced cardiac metabolism of plasma glucose in high-altitude natives: adaptation against chronic hypoxia.

The metabolism of glucose in mammalian heart is 25-50% more O2 efficient than the metabolism of free fatty acids. To assess the role of substrate preference in adaptations to chronic hypoxia, positron emission tomographic measurements of heart regional glucose uptake rates after an overnight fast were made in volunteer Quechua subjects and in Sherpa subjects, both indigenous to altitudes of over 3,000 m, and in a group of lowlander volunteers. Highest uptake rates were found in the Quechuas on arrival and in the Sherpas after a 3-wk period at low altitude, intermediate rates in Quechuas after a 3-wk period at low altitude and in the lowlanders, and lowest rates in Sherpas on arrival. These low values were probably related to the stress of travel to the site of the experiments. Measured plasma catecholamines, hormones, and substrates indicated that glucose concentrations correlated best with observed variations in glucose uptake, with a negative correlation for the control subjects and a positive correlation for the Quechuas and Sherpas. Uptake values in Quechuas declined significantly after a 3-wk period at low altitude, but the positive correlation with glucose levels persisted. We conclude that an elevated glucose preference in heart is a true metabolic adaptation in humans adapted over generations to chronic hypoxia.

Adaptation, Physiological↗

PubMed1994

Synthesis of the fluorine-18 labeled inhalation anesthetics.

Fourteen compounds (fluoroalkanes and fluoroethers), including the two most utilized inhalation anesthetics Isoflurane (CF3CHClOCF2H) and Halothane (CF3CHBrCl), have been labeled with fluorine-18 via a facile 18F-for-19F exchange reaction. The compounds include ten inhalation anesthetics which span a ten-fold range in potency and four structurally related non-anesthetics. All the compounds possess a trifluoromethyl group (CF3) adjoining a carbon atom with an acidic alpha-hydrogen and at least one halogen or a strong electron withdrawing group (X), [CF3CHXR]. We postulate the isotopic fluoride exchange reaction proceeds through a carbanion transition state resulting from alpha-proton transfer to base. The carbanion stability is attributed to the inductive effect of the CF3 group and the electron withdrawing capability of X. Compounds labeled in dimethyl sulfoxide (DMSO) at 125 degrees C in 15 min include Isoflurane-CF3CHClOCF2H (1) (97% [18F]fluorine incorporation, 99% radiochemical purity, respectively), Sevoflurane-CF3CHCF3OCFH2 (2) [98%, 99%], CF3CHBrOCF2H (3) [85%, 80%], Desflurane-CF3CHFOCF2H (4) [50%, 99%], Fluroxene-CF3CH2OCH = CH2 (5) [25%, 99%], Fluothyl-CF3CH2OCH2CF3 (6) [60%, 10% at a temperature of 175 degrees C], Halothane-CF3CHBrCl (7) [98%, 95%], CF3CH2I (8) [99%, 98%], CF3CH2Br (9) [18%, 98%], CF3CHCl2 (10) [95%, 98%], CF3CH2Cl (11) [90%, 20%], CF3CHClCF3 (12) [95%, 99%], (CF3)3CH (13) [99%, 99%] and HF-134a-CF3CFH2 (14) (15%, 93% at a temperature of 175 degrees C).

Anesthetics, Inhalation↗

PubMed1994

The brain at high altitude: hypometabolism as a defense against chronic hypoxia?

The brain of hypoxia-tolerant vertebrates is known to survive extreme limitations of oxygen in part because of very low rates of energy production and utilization. To assess if similar adaptations may be involved in humans during hypoxia adaptation over generational time, volunteer Quechua natives, indigenous to the high Andes between about 3,700 and 4,900 m altitude, served as subjects in positron emission tomographic measurements of brain regional glucose metabolic rates. Two metabolic states were analyzed: (a) the presumed normal (high altitude-adapted) state monitored as soon as possible after leaving the Andes and (b) the deacclimated state monitored after 3 weeks at low altitudes. Proton nuclear magnetic resonance spectroscopy studies of the Quechua brain found normal spectra, with no indication of any unusual lactate accumulation; in contrast, in hypoxia-tolerant species, a relatively large fraction of the glucose taken up by the brain is released as lactate. Positron emission tomographic measurements of [18F]2-deoxy-2-fluoro-D-glucose (FDG) uptake rates, quantified in 26 regions of the brain, indicated systematically lower region-by-region glucose metabolic rates in Quechuas than in lowlanders. The metabolic reductions were least pronounced in primitive brain structures (e.g., cerebellum) and most pronounced in regions classically associated with higher cortical functions (e.g., frontal cortex). These differences between Quechuas with lifetime exposure to hypobaric hypoxia and lowlanders, which seem to be expressed to some degree in most brain regions examined, may be the result of a defense adaptation against chronic hypoxia.

Adaptation, Physiological↗

PubMed1994

Cerebral vasocapacitance in human aging.

To show a relationship between age and cerebral blood flow as well as between age and cerebral vasocapacitance to induced hypercapnia or cerebral reserve percentage, positron emission tomography (PET) with fluorine-18-fluoromethane was used to study 36 normal subjects and 36 patients, all free of stroke, who presented with transient ischemic attacks in a unilateral carotid distribution. Symptomatic-side data have been published elsewhere. All asymptomatic carotid arteries were either normal or had nonstenotic plaque, and subjects were free of intracranial stenoses. Cerebral blood flow and cerebral reserve percentage were calculated for both middle cerebral artery flow territories. Serum hematocrit, expired carbon dioxide tension, and mean arterial blood pressure did not distinguish the two groups of patients or show an age effect. For the 72 normal nonstenotic sides in the volunteers, linear regression showed that while increasing age was significantly related to decreasing cerebral blood flow in the middle cerebral artery, there was no particular relationship between age and decreasing cerebral reserve percentage. In patients, while no overwhelming linear relationships were found between age and decreases in either cerebral blood flow or cerebral reserve percentage, the latter values approached significance as declining cerebral reserve percentage did relate to increasing age. Over a 60-year range in normal subjects, cerebral blood flow declined 37% with age; there was a 21% age-related decrease when normal subjects 50 years and younger were compared to those 50 years and older.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Acute changes in glucose uptake after treatment: the effects of carmustine (BCNU) on human glioblastoma multiforme.

Sequential positron emission tomographic scans with [18F]-2-fluorodeoxyglucose (PET-FDG) were performed on 6 patients with glioblastoma multiforme who were treated with adjuvant BCNU. Scans were acquired before and 24 hours after BCNU. All patients had prior brain irradiation. Ratios between the maximal tumor FDG uptake and the contralateral white matter FDG uptake, the glucose uptake ratio, were determined. Percent changes in the glucose uptake ratio between the baseline scan and the 24 hour post-treatment scan were of prognostic significance. Patients with the largest percent changes in FDG uptake had the shortest survival. In contrast, neither the baseline glucose uptake ratio nor the visual tumor grade accurately predicted length of survival.

Biological Transport, Active↗

PubMed1993

Technetium-94m-teboroxime: synthesis, dosimetry and initial PET imaging studies.

Technetium-94m (T1/2 = 53 min) allows the in vivo study of technetium radiopharmaceuticals with positron emission tomography (PET). PET provides a quantitative assay of radioactivity with excellent temporal and spatial resolution, revealing biodistributions that were previously available only through in vitro assay methods. Technetium-94m, produced by the proton irradiation of natural molybdenum on an 11 MeV cyclotron, was extracted with an electrochemical etching technique. Technetium-94m-pertechnetate was prepared to make the myocardial perfusion agent teboroxime in an identical manner as 99mTcO4-. The increased absorbed radiation dose requires a sevenfold reduction in administered activity compared to 99mTc-teboroxime. Eleven clinical PET studies were performed and visually compared to 13N-ammonia. The clearance half-time for 94mTc-teboroxime was approximately 8 min, with a peak myocardial extraction of approximately 3% of the injected dose into a 400-g heart. These results confirm the potential of 94mTc PET for quantitatively studying the pharmacokinetics of new, and old, technetium agents in man.

Adult↗

PubMed1992

[18F]fluoro-beta-fluoromethylene-m-tyrosine analogs, potential PET agents for presynaptic dopamine terminals: synthesis and spectroscopic characterization.

18F-labeled (E)-beta-fluoromethylene-DL-m-tyrosine (FMMT) was prepared by the direct reaction of FMMT with [18F]acetylhypofluorite (AcOF) resulting into three product isomers. Extensive 1H, 13C and 19F-NMR spectroscopic analysis identify these products to be 2-fluoro, 6-fluoro-FMMT and 2,6-difluoro-FMMT. The HPLC isolated radiochemical EOB yields of these products were 22, 25 and 14%, respectively, based on starting [18F]AcOF. The specific activity at the end of a synthesis time of an hour was ca 200 mCi/mmol. With the possible advantage of "metabolic trapping" in dopamine nerve terminals via covalent binding to MAO and reduced metabolite formation, [18F]F-FMMT may potentially be the optimal PET tracer for CNS dopamine nerve terminals.

Brain↗

PubMed1992

Blood flow asymmetry in carotid occlusive disease.

Patterns of anterior border zone (ABZ) and middle cerebral artery (MCA) cerebral blood flow (CBF) asymmetry were readily seen during both normocapnic room air (RA) and induced hypercapnic (CO2) inhalation using fluoro-methane and a multislice, high-resolution positron scanner. Wilcoxon two-sample rank testing showed symptomatic-over-nonsymptomatic CBF ratios for unilateral greater than 75% carotid stenosis patients (n = 8) to be 1.05 +/- 0.07 (p less than 0.008 as compared with control of 0.97 +/- 0.02) ABZ RA, 0.98 +/- 0.11 ABZ Co2, 0.98 +/- 0.04 MCA RA, and 0.98 +/- 0.06 MCA CO2. Unilateral carotid occlusion patients (n = 8) had ratios of 0.90 +/- 0.16 ABZ RA, 0.81 +/- 0.19 (p less than 0.002) ABZ CO2, 0.90 +/- 0.12 and 0.89 +/- 0.13 for MCA RA and CO2, respectively (both p less than 0.008 as compared with control 0.99). These preliminary results suggest an upgrade of autoregulation (ie, very high ratio) in the ABZ of high-grade stenosis patients during normocapnia. CBF was preferentially higher on the symptomatic side and then either did not increase or paradoxically fell in response to hypercapnia. In comparison, carotid occlusion patients had low ABZ and MCA ratios during normocapnia, also unable to increase with hypercapnia. The fall in ratios from normocapnia to hypercapnia indicates that these areas, already subject to maximal vasodilation, fail to increase CBF or actually become hypoperfused following induced hypercapnia. These results aid in understanding the concept of "hemodynamic significance."

Aged↗