Intra-individual comparison of 3(R)-BMIPP and 3(S)-BMIPP isomers in humans

The racemic 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) is currently used at several centers for myocardial metabolic imaging with SPECT. Recently, the 3(R)-BMIPP isomer showed a 20%-25% higher myocardial uptake and lower liver uptake than 3(S)-BMIPP in fasted rats. The aim of this study was to determine if these differences in myocardial and liver uptake also occur in humans. METHODS: Iodine-123-labeled 3(R)-BMIPP and 3(S)-BMIPP isomers were injected at rest, on two separate days, in six patients with stable coronary artery disease. Dual-head, whole-body scintigraphy was performed 20 min and 3 hr after injection. SPECT cardiac imaging was performed 60 min after injection. RESULTS: Myocardial activity averaged (% injected dose +/- s.d.) 3.15 +/- 0.49 versus 3.01 +/- 0.44 at 20 min (p = ns) and 2.64 +/- 0.38 versus 2.55 +/- 0.41 at 3 hr postinjection (p = ns) for the 3(R)-BMIPP and 3(S)-BMIPP isomers, respectively. Liver activity averaged 9.50 +/- 1.18 versus 9.44 +/- 0.66 at 20 min and 5.33 +/- 0.64 versus 5.43 +/- 0.66 at 3 hr, respectively (p = ns). SPECT showed no difference in the distribution of the two isomers between normal and infarcted myocardium. CONCLUSION: There is no significant difference in myocardial and liver distribution of the 3(R)-BMIPP and 3(S)-BMIPP isomers in humans.     

Evaluation of myocardial perfusion and fatty acid uptake using a single injection of iodine-123-BMIPP in patients with acute coronary syndromes

The purpose of this study was to clarify the possibility of simultaneous evaluation of myocardial perfusion and fatty acid metabolism using a single injection of 123I-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) in patients with acute coronary syndromes. METHODS: Thirty patients with unstable angina pectoris (UAP group) and 15 patients with acute myocardial infarction (MI group) were studied. BMIPP dynamic SPECT was performed 2 min after the injection of BMIPP (185 MBq), and images were obtained every 3 min for 15 min with a three-head gamma camera. Conventional BMIPP SPECT was also performed 30 min after the injection. Serial BMIPP and resting 201TI images were compared. RESULTS: A 201TI-BMIPP mismatch between 30-min BMIPP and resting 201TI images was observed in 27 of 30 patients in the UAP group and 8 of 15 patients in the MI group, respectively. However, a 201TI-BMIPP mismatch between early (2-5-min) BMIPP and resting 201TI images was observed in only 2 of 30 patients in the UAP group and in only 2 of 15 patients in the MI group, respectively. The kappa statistics of tracer uptake between early BMIPP and resting 201TI images showed good concordance in UAP (kappa = 0.823) and MI (kappa = 0.765) groups, respectively. These results indicated that initial distribution of BMIPP reflects myocardial perfusion in patients with acute coronary syndromes. CONCLUSION: Myocardial perfusion and fatty acid metabolism can be evaluated simultaneously using a single injection of BMIPP, when images are taken soon (2-5 min) and long after the injection in patients with acute coronary syndromes.     

Extraskeletal primary osteosarcoma of the frontal region]

This article presents two cases with preserved myocardial 201Tl uptake and absent uptake of two kinds of radioiodinated fatty acids: iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and iodine-123-labeled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA). Although coronary angiography showed no stenotic lesion and left ventriculography revealed no wall motion abnormality, no myocardial uptake of BMIPP and 9MPA was observed in the first case. In the second case, no myocardial accumulation was recognized even in the initial phase of dynamic SPECT acquired soon after the injection of 9MPA. The results suggest that the non-visualized myocardium was not specific for BMIPP imaging and that rather than the early back diffusion of the tracers from the myocardium, abnormality of the myocardial cell membrane was a possible mechanism accounting for the phenomenon.     

Pharmacological evaluation of [11C]A-84543: an enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors

[11C]A-84543, 3-[(1-[11C]methyl-2(S)-pyrrolidinyl)methoxy]pyridine, is a specific and enantioselective neuronal nicotinic acetylcholine receptor (nAChR) radiotracer. The in vivo biodistribution of this radiotracer in mice showed high brain uptake and a distribution consistent with the density of nAChRs. Highest uptake was observed in the thalamus (9.6 %ID/g), cortex (9.9 %ID/g), superior colliculus (7.6 %ID/g) and hippocampus (7.6 %ID/g) at 5 min followed by clearance. As a measure of specificity, the thalamus/cerebellar ratio reached a maximum of 2.3 at 30 min post-injection. Radioactivity in the thalamus and superior colliculus was reduced by 33% by pre-administration of unlabeled A-84543. The nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced the radioactivity due to [11C]A-84543 in the superior colliculus by 41%, 38%, and 27%, respectively, while lobeline, which also interacts with central nAChRs, produced a 24% inhibition. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect on [11C]A-84543 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D2/sigma) also displayed no inhibitory effect in any brain region studied. With the pharmacologically less active enantiomer, 3-[(1-[11C]methyl-2(R)-pyrrolidinyl)methoxy] pyridine, high brain uptake was also observed, but with a low thalamus/cerebellar ratio of 1.4 at 30 min post-injection. [11C]A-84543 displays enantioselectivity for nAChRs and may deserve further investigation as a possible PET radiotracer.     

Evaluation of myocardial uptake of beta-methyl-(123I)-iodophenylpentadecanoic acid (123I-BMIPP)

To evaluate the myocardial uptake of beta-methyl-(123I)-iodophenylpentadecanoic acid (123I-BMIPP), nineteen patients with ischemic heart disease including left ventricular hypertrophy (mean age 63 +/- 7.8, 14 males and 5 females) underwent BMIPP myocardial scintigraphy. Myocardial uptake (MU) of BMIPP to the total injected dose was calculated from anterior view of the planar image in all subjects, and was compared with plasma glucose (BS), triglyceride (TG), and free fatty acid (FFA). It was also compared with left ventricular mass (LVM) calculated with echocardiography. MU was not related to BS, TG, and FFA, however had the positive correlation with LVM (r = 0.676, p < 0.01). Myocardial uptake per left ventricular mass (MU/LVM) had the negative correlation with LVM (r = -0.671, p < 0.01). Further studies for the significance of MU/LVM will be required.     

5-[I-125/123]lodo-3(2(S)-azetidinylmethoxy)pyridine, a radioiodinated analog of A-85380 for in vivo studies of central nicotinic acetylcholine receptors

The in vivo biodistribution profile of the novel nicotinic acetylcholine receptor (nAChR) radioligand 5-[I-125/123]Iodo-3(2(S)-azetidinylmethoxy)pyridine, [I-125/123]-5-IA, in mouse brain was examined. This radiotracer displayed good brain penetration (3.1% of the injected dose (ID) in whole brain at 15 min post-radioligand injection). Radioligand distribution was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus (14.9 %ID/g at 60 min), moderate uptake in cortex (8.5 %ID/g at 60 min), and lowest uptake in the cerebellum (2.4 %ID/g at 60 min). Pretreatment with several different nAChR agonists (A-85380, (-)-nicotine, cytisine) significantly inhibited [I-125]-5-IA binding in all brain regions studied (P < 0.01) demonstrating the high specificity of the radioligand for nAChRs. Blocking doses of the muscarinic antagonist scopolamine and the non-competitive nAChR channel blocker mecamylamine had no significant effect on radioactive uptake supporting the in vitro selectivity of [I-125]-5-IA for the nAChR component of the cholinergic system. [I-125]-5-IA binding sites were shown to be saturable with unlabeled 5-IA. With a relatively low acute toxicity (LD50 > 3 mg/kg via intravenous injection in mice) and high in vivo specificity and selectivity, 5-IA labeled with the imaging radionuclide I-123 may prove useful for single photon emission computed tomography (SPECT) studies of nAChRs in human subjects.     

Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia

To study the sensitivity of two fatty acid tracers to changes in beta-oxidation, the myocardial retention kinetics of 125I-iodine-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) and 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) were compared in states of oxygen deprivation due to ischemia and hypoxia. METHODS: Nineteen swine were studied by extracorporeal perfusion of the three coronary arteries. Fatty acid beta-oxidation rates were determined by infusion of tritiated palmitate into the left anterior descending artery (LAD) and by measurement of labeled water production in the LAD perfusion bed. After a baseline period of 30 min, animals were divided into three groups and subjected to a 50-min intervention period. For the control group, there was no change in perfusion; for the ischemia group, there was a 60% decrease in LAD perfusion; and for the hypoxia group, the perfusion rate was unchanged, but venous blood was used as the LAD perfusate. Continuous infusion of FTHA and BMIPP into the LAD started 10 min into the intervention period and continued until the end of the intervention period. Retention rates of the two tracers were compared between the LAD and circumflex perfusion beds. RESULTS: No difference in beta-oxidation rate occurred from the baseline to the intervention period in the control group. A 50% reduction in beta-oxidation occurred in the ischemia group, and an 80% reduction occurred in the hypoxia group. No difference in retention of BMIPP or FTHA occurred in the control group. In the ischemia group, reduction in retention of both tracers occurred. However, in the hypoxia group, FTHA uptake was unchanged, whereas BMIPP retention increased compared to the circumflex arterial bed. CONCLUSION: Decreased retention of both BMIPP and FTHA occurred with ischemia, despite the known differences in metabolism of the two tracers. This difference in metabolism was further highlighted in the setting of hypoxia with increased BMIPP uptake. Thus, these results suggest that uptake of both FTHA and BMIPP tracks reduction of fatty acid utilization in myocardial ischemia but fails in tracking reduction of fatty acid oxidation during hypoxia.     

Metabolism of 2,3-butanediol stereoisomers in the perfused rat liver

The identification of 2,3-butanediol in sera of alcoholics led to the hypothesis that it may be a specific marker of alcohol abuse. We have investigated the metabolism of the individual isomers of 2,3-butanediol (2R,3R-, 2S,3S-, meso-2,3-butanediol and racemic 2,3-butanediol) in perfused livers from fed rats. Rates of uptake of the isomers decrease in the order (i) 2R,3R-, (ii) meso-, (iii) 2S,3S-2,3-butanediol. We observed interconversion of isomers and oxidation to acetoin with 2R,3R- and meso- but not with 2S,3S-2,3-butanediol. In perfusions conducted in deuterium oxide, interconversion of isomers was accompanied by incorporation of deuterium. Thus, interconversion of isomers occurs via a reversible oxidation to acetoin with incorporation of hydrogen from water. In perfusions with either 2R,3R- or meso-[2-14C]2,3-butanediol, the substrates were converted to labeled acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3-butanediol is oxidized to acetyl-CoA via acetoin.     

Evaluation of Biocoat intestinal epithelium differentiation environment (3-day cultured Caco-2 cells) as an absorption screening model with improved productivity

We describe the clinical features and results of cardiac catheterization, PET ([13N]ammonia, 18F-fluorodeoxyglucose (FDG)) and SPECT [123I-labeled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP)], in a patient with acute myocardial infarction successfully treated with intracoronary thrombolytic therapy. We compared the clinical and electrocardiographic changes with the myocardial glucose and fatty acid metabolism in stunned myocardium over a period of several months. The patient we studied illustrates the features of stunned myocardium. In the subacute phase, there was a concordant depression of myocardial [13N]ammonia and FDG uptake, and the metabolic abnormalities persisted even after regional wall motion at rest had returned to normal. The electrocardiographic recovery of deep negative T waves appeared to be related to the metabolic recovery in regions of stunned myocardium in this patient.     

Studies towards the synthesis of the hypermodified nucleoside of rat liver phenylalanine transfer ribonucleic acid: improved synthesis of the base beta-hydroxywybutine

An improved synthesis of the key intermediates (3 and 8) for the synthesis of beta-hydroxywybutines [[R-(R*,S*)]- and [S-(R*,R*)]-4], the most probable structures for the minor base from rat liver tRNA(Phe), has been achieved by the Wittig reaction between 1-benzyl-7-formylwye (1) and the phosphorane derived from (R)-2-[(methoxycarbonyl)amino]-3-(triphenylphosphonio)propanoate (10), followed by methylation, OsO4 oxidation, and cyclocondensation with COCl2 in the presence of pyridine. The racemic forms of beta-hydroxywybutines [(R*,S*)- and (R*,R*)-4], which were required for the determination of the optical purity of [R-(R*,S*)]- and [S-(R*,R*)]-4 by means of chiral HPLC, were conveniently prepared through pyrolysis of the cyclic carbonate 3 followed by NaBH4 reduction and catalytic hydrogenolysis. The samples of [R-(R*,S*)]- and [S-(R*,R*)]-4 were thus shown to be optically pure.     

1 beta-Methyl-2-(5-substituted pyrrolidin-3-ylthio)carbapenems. 3. Synthesis and antibacterial activity of BO-2727 and its related compounds

The synthesis and biological activity of (1R,5S,6S)-2-[(3S,5S)- 5-substituted pyrrolidin-3-ylthio]- 6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid in which hydroxy-substituted aminoethyl, aminopropyl, and aminobutyl groups were introduced as substituents, are described. These derivatives showed potent antibacterial activity against Gram-positive and Gram-negative bacteria including P. aeruginosa. Among them, lenapenem (BO-2727, 7b), carrying an (R)-1-hydroxy-3-(N-methylamino)propyl group, was selected as a development candidate.     

Evaluation of heart-to-organ ratios of 123I-BMIPP and the dimethyl-substituted 123I-DMIPP fatty acid analogue in humans

Radioiodinated fatty acid analogues modified by methyl-substitution are used for single photon emission tomography (SPET) imaging of the heart. The effect of mono- and dimethyl-substitution on heart-to-organ ratios was investigated in humans to evaluate their relative merits for SPET image quality. Planar total body scans were performed in fasting patients with coronary artery disease, but without heart failure, 1 h after administration of 111 MBq 15-(p-[I-123]-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP, n = 7) or 111 MBq 15-(p-[I-123]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP, n = 4). Because these branched fatty acids are used for cardiac imaging, we focused on heart-to-organ (heart/organ) ratios by comparing small regions of interest in heart, liver, lung, muscle and bladder. Both tracers showed good visualization of the heart. DMIPP showed a relatively high liver uptake: the heart/liver ratios for DMIPP and BMIPP were 0.39 +/- 0.05 and 1.00 +/- 0.12, respectively (P < 0.0001). Increased lung activity was found for BMIPP, with a heart/lung ratio of 1.63 +/- 0.17 versus 2.32 +/- 0.28 for DMIPP (P < 0.001). In contrast to DMIPP, BMIPP also showed increased activity in the bladder. In conclusion, BMIPP and DMIPP show different distribution patterns. Despite the more favourable heart/lung ratios for DMIPP, the high liver uptake affects cardiac SPET image quality and therefore BMIPP appears to provide superior cardiac SPET image quality in humans.     

Antiplatelet effects of R,S-(meso)-alpha, alpha'-bis[3-(N,N-diethylcarbamoyl) piperidino]-p-xylene ex vivo in the dog and in vivo in the mouse

1. The nipecotamide alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene (A-1) is a platelet aggregation inhibitor. The meso diastereomer A-1c is superior in potency and duration to the synthetic diastereomeric mixture consisting of the R,R-, S,S-, and R,S- (meso) isomers in inhibiting collagen-induced platelet aggregation ex vivo in the dog. 2. A-1c also is more potent and longer acting than A-1 in protecting mice from collagen+epinephrine-induced thromboembolic death. 3. The mechanism of antiplatelet action of this compound appears to be related to its ability to prevent agonist-induced inhibition of platelet cyclic adenosine monophosphate (cAMP) levels.     

Comparison of uptake, oxidation and lipid distribution of 17-iodoheptadecanoic acid, 15-(p-iodophenyl)pentadecanoic acid and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid in normal canine myocardium

The kinetics of 17-[123I]iodoheptadecanoic acid (IHDA), 15-(p-[125I]iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[131I]iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPPA) were investigated in normal canine myocardium. After simultaneous intravenous injection, myocardial biopsy specimens and samples of arterial blood were taken over 80 min. IHDA showed the highest myocardial uptake (995 +/- 248 dpm/mg.mCi versus pIPPA: 785 +/- 197 dpm/mg.mCi, ns) and the largest size of oxidation (74% +/- 4% versus pIPPA: 65% +/- 5%, p < 0.05). Myocardial activity of IHDA decreased with a half-time value of 11.2 min (pIPPA: 13.2 min). Phospholipids were the main lipid fraction into which IHDA was incorporated, whereas pIPPA was predominantly incorporated into triacylglycerols. DMIPPA myocardial activity remained constant during the assay period and instead of being oxidized, DMIPPA was mainly incorporated into triacylglycerols (55% +/- 12%). The myocardium-to-blood ratios of DMIPPA were greater than 10:1. The ratios at peak for IHDA and pIPPA were 4.1:1 and 3.9:1, respectively (both p < 0.0001 versus DMIPPA). In conclusion, differences have been found in the myocardial uptake, oxidation and lipid distribution of IHDA, pIPPA and DMIPPA. DMIPPA is a promising tracer for fatty acid uptake studies with single-photon emission computerized tomography because of its prolonged retention and high myocardium-to-blood ratios.     

Outcome significance of thallium-201 and iodine-123-BMIPP perfusion-metabolism mismatch in preinfarction angina

The relevance of brief antecedent ischemia to preservation of myocyte viability and cardiac function is still controversial in humans. Dysfunctioning but viable myocardium shows impaired fatty acid metabolism despite restored coronary perfusion. We asked whether preinfarction angina might be related to preservation of cell viability and better functional recovery in comparison with impaired fatty acid metabolism. METHODS: Tomographic imagings with thallium and beta-methyl-p-iodophenyl penta-decanoic acid (BMIPP) were performed in 32 patients with first acute myocardial infarction who received primary coronary angioplasty: 20 patients with preexisting angina before infarction (Group A) and 12 without (Group B). Thallium and BMIPP abnormalities were quantified as a severity index by a polar map. Regional function was quantified by ventriculography and followed up. RESULTS: Despite no significant difference in coronary risk factors, cardiac function and angiographic findings, the thallium severity index was significantly lower than that of BMIPP (62+/-45 versus 96+/-59) in Group A but not in Group B (104+/-65 versus 115+/-68); the thallium severity index in Group A was significantly lower than that in Group B, but there was no significant difference in BMIPP abnormality between them. The BMIPP severity index correlated significantly with that of thallium in both groups. However, the regression line in Group A shifted downward and was statistically different compared with that in Group B. Regional function at an acute stage was significantly improved from 107+/-31 to 70+/-31 s.d./chord during follow-up in Group A but not in Group B (109+/-62 versus 106+/-52). The ratio of the thallium severity index to that of BMIPP at an acute stage was significantly related to improved regional wall motion during follow-up in the reperfused patients (y=-53x + 65, r=0.667). CONCLUSION: Preinfarction angina preserves myocyte viability relative to fatty acid metabolism, resulting in augmented perfusion-metabolism mismatch and functional improvement in patients undergoing successful reperfusion, indicating cardioprotective effects of preinfarction angina.     

Assessment of 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial scintigraphy in patients of chronic right ventricular overload--fatty acid metabolism in right ventricular myocardium

An investigation on the right ventricular pressure level and the abnormalities in the fatty acid metabolism of myocardium was made using 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT in patients with chronic right ventricular overloading. Twenty patients who presented with right ventricular systolic pressure (RVSP) of 35 mmHg or more were used as the subjects. Dual myocardial SPECT with 201TlCl (Tl) and BMIPP was carried out for the subjects and RVc/LVc, a ratio of radioactivity count incorporated in the right ventricular free wall to the left one was determined for Tl and BMIPP. And the correlations between RVc/LVc and RVSP, and RVc/LVc and RVSP/LVSP were examined. The subjects were classified into 3 groups based on the RVSP levels and the count ratio, BMIPP/Tl was compared among the three groups. With respect of Tl uptake, there were significant, positive correlations between RVc/LVc and RVSP (correlation coefficient r = 0.51, p < 0.05) and between RVc/LVc and RVSP/LVSP (correlation coefficient r = 0.59, p < 0.01). On the other hand, no significant correlation was found between them with respect of the uptake of BMIPP. The BMIPP/Tl ratio in the group with higher than 80 mmHg of RVSP was 0.82 +/- 0.06, which was significantly lower than the ratio's for two groups of less than 80 mmHg; 0.91 +/- 0.07 and 0.98 +/- 0.04 in the group with 35-49 and 50-79 mmHg of RVSP, respectively. These results show that when compared with BMIPP, Tl is superior for the estimation of right ventricular pressure. For the patients with right ventricular overloading, it was suggested that when RVSP reaches 80 mmHg or more, there appear some disorders in the fatty acid metabolism in the right ventricular myocardium.     

(3SR,4aRS,6SR,8aRS)-6-(1H-tetrazol-5-yl)decahydroisoquinoline-3-carboxylic acid, a novel, competitive, systemically active NMDA and AMPA receptor antagonist

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole-substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtained from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.     

Vitamin A supplementation but not deworming improves growth of malnourished preschool children in eastern Zaire

14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) has been recently introduced as a new tracer for fatty acid metabolism. Myocardial [18F]FTHA uptake is believed to reflect mainly beta-oxidation of the circulating free fatty acids (FFAs), since it is trapped in the mitochondria because subsequent steps of beta-oxidation are inhibited by sulfur heteroatom. We investigated [18F]FTHA kinetics in myocardial and skeletal muscle in vivo. METHODS: Two dynamic PET studies were performed in seven patients with stable coronary artery disease, once in the fasting state and once during euglycemic hyperinsulinemia (serum insulin approximately 60 mU/liter). The fractional [18F] FTHA uptake rates (Ki) were multiplied with serum FFA concentrations and were considered to represent FFA uptake. RESULTS: Serum FFA concentration decreased by 80% during insulin clamp. After tracer injection, rapid myocardial uptake was identified both in the fasting state and during insulin stimulation. The cardiac image quality was excellent in both occasions. In addition, femoral muscles were clearly visualized in both studies. The fractional myocardial [18F]FTHA uptake rates (Ki) in the normal myocardial regions were similar in the fasting state (0.11 +/- 0.04 ml/g/min (mean +/- s.d.) and during insulin clamp (0.12 +/- 0.03 ml/g/min; ns). The calculated myocardial FFA uptake was four times higher in the fasting state than during insulin clamp (5.8 +/- 1.7 versus 1.4 +/- 0.5 micromol/100 g/min, p < 0.005). The femoral muscle fractional [18F]FTHA uptake rates (Ki) were lower (0.0071 +/- 0.0014 ml/g/min) in the fasting state than during insulin clamp (0.0127 +/- 0.0036 ml/g/min; p = 0.03), but the estimated femoral muscle FFA uptake was three times higher in the fasting state (0.38 +/- 0.09 micromol/100 g/min) as compared to that during insulin clamp (0.12 +/- 0.05 micromol/100 g/min, p < 0.005). CONCLUSION: Fluorine-18-FTHA PET appears to be a feasible method to estimate fatty acid kinetics in myocardial and skeletal muscle. Physiologically reasonable rates of FFA uptake in myocardium and skeletal muscle were obtained. Furthermore, the uptake rates were suppressed in response to insulin both in the myocardial and femoral muscle as expected.     

Propanil affects transcriptional and posttranscriptional regulation of IL-2 expression in activated EL-4 cells

OBJECTIVE: To determine the clinical and prognostic value of identifying metabolic abnormalities of myocardial fatty acid metabolism in idiopathic dilated cardiomyopathy using iodine-123 beta-methyl-iodophenyl pentadecanoic acid (123I BMIPP). SETTING: Cardiac care division in national hospital. PATIENTS: 32 consecutive patients with idiopathic dilated cardiomyopathy in whom both 123I BMIPP and thallium-201 myocardial single photon emission computed tomography were performed. METHODS: The uptake of each tracer was scored visually from 0 (normal) to 3 (defect) in 17 segments (eight basal, eight midventricular, and one apical). A total score for all 17 segments was compared with clinicopathological variables. Prognostic value of mismatches between the two tracers were also evaluated. RESULTS: The 123I BMIPP total score was correlated with pulmonary capillary wedge pressure (r = 0.68, p < 0.001), left ventricular end diastolic pressure (r = 0.65, p < 0.001), percentage fractional shortening at six months' follow up (r = -0.58, p = 0. 001), myocyte diameter (r = 0.66, p < 0.001), and percentage area of interstitial fibrosis (r = 0.69, p < 0.001) measured by morphometry in the biopsy specimens. During a mean (SD) follow up of 20 (11) months, deterioration of the New York Heart Association functional class was observed in 11 of the 32 patients; four of these died. Segments with a greater decrease in 123I BMIPP than thallium-201 uptake (type B mismatching) were often observed in patients with deterioration (88/187, 29% v 58/357, 16%; p < 0.001). CONCLUSIONS: The extent of the abnormality of myocardial fatty acid metabolism in idiopathic dilated cardiomyopathy reflects the severity of haemodynamic deterioration and histopathological changes. Type B mismatching is one of the important prognostic indicators in idiopathic dilated cardiomyopathy.     

Synthesis and inhibitory action on HMG-CoA synthase of racemic and optically active oxetan-2-ones (beta-lactones)

A homologous series of both C3-unsubstituted and C3-methyl substituted oxetan-2-ones (beta-lactones) was investigated as potential inhibitors of yeast 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase. Several reported methods for racemic beta-lactone synthesis were studied for preparation of the target series. In addition, a novel aluminum-based Lewis acid obtained by combination of Et2AlCl with (1R,2R)-2-[(diphenyl)hydroxymethyl] cyclohexan-1-ol was studied for the asymmetric [2 + 2] cycloaddition of aldehydes and trimethylsilylketene. This Lewis acid exhibited good reactivity but variable enantioselectivity (22-85% ee). In in vitro assays using both native and recombinant HMG-CoA synthase from Saccharomyces cerevisiae, oxetan-2-ones mono-substituted at C4 with linear alkyl chains gave IC50s that decreased monotonically with chain length up to 10 carbons and then rose rapidly for longer chains. The trans isomers of 3-methyl-4-alkyl-oxetan-2-ones showed a similar trend but had 1.3- to 5.6-fold lower IC50s. The results imply a substantial hydrophobic pocket in this enzyme that interacts with both C-3 and C-4 substituents of oxetan-2-one inhibitors.