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Biomedical subjects

J S Fowler

Publications and source records attributed to J S Fowler.

At least 217 records · Page 12Linked to original sources
PubMed1986

Renal toxicity of propyleneimine: assessment by non-invasive techniques in the rat.

The nephrotoxicity of three different dose levels of propyleneimine (10, 20 and 30 microliter/kg body wt) administered intraperitoneally to rats was studied and 20 microliters/kg body weight was found to be the most appropriate sublethal dose. Injection of propyleneimine (10 microliters/kg body wt) produced a small rise in N-acetyl-beta-D-glucosaminidase (NAG) activity, minor histological damage but no change in urine volume. Six rats were injected with 20 microliters/kg body weight, and urine was collected over the following 16 days. An immediate increase in urine volume, osmolality together with a concomitant decrease in specific gravity, was accompanied by a small increase in creatinine excretion and a more marked increase in the sodium and potassium content of urine after the administration of the nephrotoxin. NAG activity increased immediately and peaked on day 3, the activity remained elevated until day 12 when it fell to near normal levels. The activity of both beta-D-galactosidase and beta-D-glucosidase increased 9 days after administration of the nephrotoxin. In contrast, no consistent change was found in the excretion of the brush border marker enzymes, leucine aminopeptidase (LAP), alanine aminopeptidase (AAP) or alkaline phosphatase (ALP). Proteinuria increased sharply the day after injection and remained abnormal. Increased urinary albumin excretion and the predominance of low molecular weight proteins was demonstrated by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. Evidence is presented that propyleneimine exerts its early toxic effect on the renal papilla.

Acetylglucosaminidase↗
PubMed1986

Modular automation in PET tracer manufacturing: application of an autosynthesizer to the production of 2-deoxy-2-[18F]fluoro-D-glucose.

A compact autosynthesizer was developed and used successfully for the production of 2-deoxy-2-[18F]fluoro-D-glucose [18FDG] from gaseous acetyl hypo[18F]fluorite. The autosynthesizer performs a sequence of general purpose synthesis procedures named Synthesis Unit Operations (SUO's). Each SUO is controlled through execution of a digital control algorithm with a BASIC language subroutine. This automatic synthesis system is based on two industry standard microcomputer architectures, the IBM PC and STD Bus, and it becomes a component of an evolving distributed microprocessor network of task-dedicated subsystems suitable for automated manufacturing of several useful radiotracers. The yield of 18FDG product using the autosynthesizer and remote manually controlled purification procedures is approximately 20% EOB. Radiochemical purity of this product as measured by thin layer chromatography was 96-99%. Chemical purity of the product was measured to be approximately 96%. 2-Deoxy-2-fluoro-D-mannose impurity from this method was determined to be approximately 4%.

Deoxy Sugars↗
PubMed1986

A direct comparison of the brain uptake and plasma clearance of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol in baboon using PET.

Serial PET studies of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol were carried out in a single baboon with an intervening time period of 2 h between injection of the 11C and the 18F-labeled tracers. The kinetic patterns of uptake and egress of radioactivity in striatum and cerebellum as well as the magnitude of the uptake was very similar with the two tracers. In addition, no significant difference in clearance of total radioactivity from arterial plasma was detected. Analysis of plasma radioactivity for unchanged drug showed no significant differences in the amount of unchanged tracer at different times, although the profile of labeled metabolites was different. These results indicate that the only significant difference between the use of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol for PET studies of brain dopamine receptors relate to the difference in physical half-life of the radionuclide rather than to differences in the profile of metabolically produced labeled compounds.

Animals↗
PubMed1986

Improved delineation of human dopamine receptors using [18F]-N-methylspiroperidol and PET.

The brain uptake of [18F]-N-methylspiroperidol, a butyrophenone neuroleptic with high selectivity for the dopamine receptor, has been measured in three normal human volunteers using positron emission tomography for times up to 12 hr postinjection. These studies demonstrated two unique findings concerning the in vivo distribution of this neuroleptic: (a) it is tightly bound to dopamine D-2 receptors in the caudate-putamen brain regions, and (b) these regions are the only large brain structures which exhibit appreciable long-term retention. In addition, radioactivity clears rapidly from plasma, and the percentage of unchanged [18F]-N-methylspiroperidol in plasma declines rapidly. These results suggest that this compound binds irreversibly to dopamine D-2 receptors, and that there are few if any dopamine D-2 receptors in the human frontal cortex. These studies emphasize not only the importance of characterizing neurotransmitter receptors in living human brain using a ligand labeled with a positron emitting nuclide of sufficiently long half-life to allow monitoring of brain radioactivity distribution for several hours after the injection of radioligand, but also of accurately determining the amount of unchanged tracer in plasma for tracer kinetic modeling.

Adult↗
PubMed1986

No-carrier-added fluorine-18-labeled N-methylspiroperidol: synthesis and biodistribution in mice.

No-carrier-added fluorine-18- (18F) labeled N-methylspiroperidol (4) was synthesized from four different substrates: p-nitrobenzonitrile (1), cyclopropyl p-nitrophenyl ketone (2A), p-cyclopropanoyl-N,N,N-trimethylanilinium iodide (2B) and p-cyclopropanoyl-N,N,N-trimethylanilinium perchlorate (2C) using the nucleophilic aromatic substitution reaction. Radiochemical yield, synthesis time, experimental simplicity, and specific activity were compared. In addition, factors which influence the yield of the nucleophilic aromatic substitution were studied. Based on these studies, the synthesis of 4 from 2A maximizes product specific activity and experimental simplicity and provides 4 in 10-15% radiochemical yield [based on [18F-] with a mass of less than 2 nmol and a specific activity of greater than 10 Ci/mumol (EOB)]. The synthesis of 4 from 8-[4-(4-nitrophenyl)-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro+ ++ [4.5]decan-4-one (5) and Cs[18F] using the nucleophilic aromatic substitution reaction gave unacceptably low and erratic yields. The biodistribution of 4 in mice showed a maximum brain uptake of 1.1% of the administered dose at 5 min and declined to approximately 0.6% at 120 min.

Animals↗
PubMed1985

[18F]-N-Methylspiroperidol: the radioligand of choice for PETT studies of the dopamine receptor in human brain.

N-Methylspiroperidol, the amide N-methyl analogue of the neuroleptic spiroperidol, was radiolabeled with fluorine-18, and its distribution in the baboon brain was studied using positron emission transaxial tomography. Stereospecific binding was demonstrated in the striatum (but not in the cerebellum) by pretreatment with (-)- or (+)-butaclamol. The kinetic distribution was similar to that of [18F]spiroperidol, but the absolute striatal uptake (in percent of administered dose) was at least two-fold higher. Analysis of baboon blood at 10 min after injection indicated that less than half of the radioactivity in the plasma was due to unchanged radioligand. Analysis of the metabolic stability of [18F]-N-methylspiroperidol in rat brain for 4 hr indicated that, like [18F]spiroperidol, it is very stable to metabolic transformation in the rat central nervous system. Striatal uptake and retention in the rat was five-fold higher for [18F]-N-methylspiroperidol than for [18F]spiroperidol. These results suggest that [18F]-N-methylspiroperidol is an ideal choice for studies of the dopamine receptor in humans.

Animals↗
PubMed1985

Synthesis of 15O-labeled butanol via organoborane chemistry.

Oxygen-15 labeled 1-butanol and 2-butanol were prepared by the reaction of O2-15O with tri-n-butylborane and tri-sec-butylborane in tetrahydrofuran. The reaction products were isolated and identified via reversed-phase high performance column chromatography and gas chromatography. Radiochemical yields of 50% (EOB) were obtained. The use of 15O-labeled butanol is suggested for cerebral blood flow measurements in conjunction with PET.

Boranes↗
PubMed1985

Comparison of three 18F-labeled butyrophenone neuroleptic drugs in the baboon using positron emission tomography.

The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

Animals↗
PubMed1985

Syntheses and specific activity determinations of no-carrier-added (NCA) F-18-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone.

A general method for the syntheses of no-carrier-added (NCA) 18F-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone is described. These 18F-labeled neuroleptic drugs are synthesized by a multistep synthesis in an overall radiochemical yield of 10-20% at end of bombardment (EOB) in a synthesis time of 90 min from EOB. The sequence involves the synthesis of NCA p-[18F]fluorobenzonitrile from NCA [18F]-fluoride and p-nitrobenzonitrile using the rapidly converted to gamma-chloro-p-[18F]fluorobutyrophenone which is alkylated with appropriate amines to give NCA 18F-labeled benperidol, haloperidol, spiroperidol, and pipamperone. The final product is purified by preparative high performance liquid chromatography (HPLC). The 18F solution used in the synthesis as determined by ion chromatography contains 15.3 +/- 9.0 nmol of stable fluoride. The specific activities of the resulting butyrophenone neuroleptics were determined to be 3 Ci/mumol (at EOB) (range 1-6 Ci/mumol) as determined by radioreceptor assay and HPLC assay.

Antipsychotic Agents↗
PubMed1985

N-(3-Fluoropropyl)-N-normetazocine, a potentially useful opiate antagonist for opiate receptor studies with positron emission tomography (PET).

A new fluorinated derivative of N-propylnormetazocine, N-(3-fluoropropyl)-N-normetazocine (1) was synthesized. 1 was similar to the unfluorinated analog 3 in its ability to compete with (3H)-naltrexone for binding sites in rat brain membranes and its potency in antagonizing morphine analgesia in rats. Competition of both compounds against (3H)-naltrexone was little affected by the presence of sodium chloride, a characteristic frequently exhibited by opiate antagonists. Morphine analgesia in rats was measured by suppression of locomotion and vocalization responses to footshock. The ability of 1 to antagonize morphine analgesia in rats was similar to that of 3. Neither 1 nor 3 showed any evidence of agonist activity in rats at doses as high as 1.0 mg/kg (the highest dose tested). These results suggest that 1, labeled with 18F, may be useful for in vivo studies of the opiate receptor using positron emission tomography (PET).

Analgesics↗
PubMed1985

Synthesis and biodistribution of no-carrier-added [1-11C]putrescine.

No-carrier-added [1-11C]putrescine was synthesized in 20% radiochemical yield in a synthesis time of 50 min by the Michael addition of potassium [11C]cyanide to acrylonitrile followed by reduction of the [11C]dinitrile with borane-methyl sulfide complex. Biodistribution in mice at 5, 30, and 60 min showed low uptake in normal brain tissue.

Animals↗
PubMed1985

Red cell population distributions in healthy dogs.

Red blood cells population distributions were studied in puppies and in mature beagle dogs using the Coulter Channelyzer C-1000. Weekly measurements over a period of six months indicated that only minor fluctuations in population distribution indices occurred. Normal range studies showed that although mean cell volume was similar in young and older dogs, young dogs showed an approximately 12.5 per cent greater volume range due to an increased presence of both larger and smaller cells. The red cell population distributions conformed to a single log normal distribution. A mild anaemia was induced in mature dogs. Compensation for this led to transient changes from the usual log normal shape of the red cell population distribution.

Anemia↗
PubMed1984

Regional brain glucose metabolism in chronic schizophrenia. A positron emission transaxial tomographic study.

Thirteen diagnosed schizophrenics and 11 normal controls were studied with a method using the PETT III positron emission tomograph (PET) and fluorodeoxyglucose labeled with fluorine 18. Each subject also had a computed tomographic (CT) scan. For each subject, two brain levels, one through the basal ganglia and one through the semioval center, were analyzed for the mean regional metabolic glucose rate. Specifically, relationships between frontal and posterior regions were evaluated. The CT scans of matching levels were superimposed on the functional PET images to provide anatomic criteria for region of interest selection. While no whole-slice metabolic differences were apparent between groups, schizophrenics had significantly lower activity in the frontal lobes, relative to posterior regions. The medicated and drug-free groups did not differ from one another in these regards. Trait v state dependency of the phenomenon was analyzed, and several technological limitations were considered.

Adult↗
PubMed1984

Patterns of metabolic activity in the treatment of schizophrenia.

Six patients with chronic schizophrenia were studied with positron emission tomography (PET) before and after neuroleptic treatment, using fluorine-18-labeled fluorodeoxyglucose. After treatment, the mean whole-slice glucose metabolic rate at the level of the basal ganglia showed a 25% increase. However, patterns of frontal hypometabolism observed with the schizophrenic patients were not altered by medication. Pattern analysis using the fast Fourier transform was applied to a set of 422 images from a mixed group of normal, depressed, and schizophrenic subjects. Reconstruction of the images with low-frequency coefficients was excellent, reducing considerably the number of variables needed to characterize each image. Hierarchical cluster analysis categorized the transformed images according to anatomical level and subject group (patient versus control). The results suggest the utility of this procedure for the classification and characterization of metabolic PET images from psychiatric patients.

Adult↗
PubMed1984

Positron emission tomography and computed tomography assessments of the aging human brain.

The relationship between alterations in brain structure and brain function was studied in vivo in both young and elderly human subjects. Computed tomography revealed significant age-related ventricular and cortical sulcal dilatation. The cortical changes were most closely related to age. Positron emission tomography failed to show regional changes in brain glucose metabolic rate. The results suggest that the normal aging brain undergoes structural atrophic changes without incurring regional metabolic changes. Examination of the correlations between the structural and the metabolic measures revealed no significant relationships. These data are discussed with respect to the significant structure-function relationships that have been reported in Alzheimer disease.

Adult↗