Hiroshi Fukuda

AGE-RELATED CHANGES IN HUMAN D1 DOPAMINE RECEPTORS MEASURED BY POSITRON EMISSION TOMOGRAPHY

The effects of age on the binding parameters of11C-SCH23390, the highly selective ligand for central D1 dopamine receptors, at specific binding sites in the brain were studied. Seventeen healthy male volunteers (20–72 years old) participated. Regional radioactivity in the brain was followed for 40 min by positron emission tomography (PET). A high accumulation of radioactivity was observed in the striatum and there was a conspicuous accumulation in the neocortex. A two-compartment model was used to obtain quantitative estimates of rate constants of association (k3) and dissociation (k4). The binding potential (k3/k4) of the dopamine D1 receptors in the striatum and frontal cortex decreased by 35% and 39%, respectively, with age. The value of k3 decreased by 58% in the striatum and 83% in the frontal cortex, whereas the value of k4 decreased by 35% in the striatum and 72% in the frontal cortex with age.

D1 dopamine receptor binding in mood disorders measured by positron emission tomography

D1 dopamine receptor binding in mood disorders was studied by positron emission tomography (PET) using11C-SCH23390. Ten patients with bipolar mood disorders and 21 normal controls were studied in the drug-free state. The patients were in euthymic (N=6), depressed (N=3) and manic (N=1) states. Regional radioactivity in the brain was followed for 40 min by PET. A two-compartment model was used to obtain the binding potential (k3/k4) for the striatum and frontal cortex. The binding potentials for the frontal cortex for the patients were significantly lower than those for normal controls, whereas those for striatum were not significantly different. These findings suggest that D1 dopamine receptors in the frontal cortex may be in a different state in patients with bipolar mood disorders.

Lung as reservoir for antidepressants in pharmacokinetic drug interactions

BACKGROUNDnAlthough high-affinity imipramine binding sites have been reported in both rat and human lung, the role of the lungs in the pharmacokinetics of antidepressants has not received much attention. Substantial accumulation of selective serotonin-reuptake inhibitors (SSRIs) in the lungs has been reported. We have investigated the role of the lungs in pharmacokinetic drug interactions between tricyclic antidepressants and SSRIs.nnnMETHODSnWe used a carbon-11-labelled form of the imipramine derivative cyanoimipramine to measure uptake in the lungs and brain of healthy volunteers by positron emission tomography. Clomipramine (50 mg) was administered to measure the effect of antidepressants with high affinity for the serotonin transporter on lung and brain uptake.nnnFINDINGSnA large proportion of the injected 11C-cyanoimipramine (68-86% in the four volunteers) was extracted by the lungs. Clomipramine decreased the lung uptake from 68% to 35% and from 81% to 54% in the two volunteers studied. By contrast, whole-brain uptake was low in control studies (1.7-2.0% in three volunteers) and increased after clomipramine administration (to 4.5-4.9%). Plasma radioactivity was also higher after clomipramine than in control studies.nnnINTERPRETATIONnThe lungs may function as a reservoir for antidepressants with high affinity to the serotonin transporter. The accumulated antidepressants may be displaced by other antidepressants, and this displacement would substantially increase plasma concentrations and thus cause toxic effects.

Frequency of Provoked Coronary Spasms in Patients Undergoing Coronary Arteriography Using a Spasm Provocation Test Via Intracoronary Administration of Ergonovine

There are no data concerning the incidence of provoked coronary arterial spasms via intracoronary administration of ergonovine (ER). This study sought to establish the incidence of spasms due to intracoronary injection of ER in Japanese patients who underwent coronary angiography. The subjects were 596 consecutive patients (369 men, mean age 64.2 ±10.3 years) who were studied with a selective ER test. ER was administered in total doses of 40 µg into the right coronary artery and 64 µg into the left coronary artery. A positive spasm was defined as a total or subtotal occlusion. Coronary vasospasms were determined in 173 patients (29.0%). Spasms occurred often in patients with ischemic heart disease (43.3%); during effort and rest in patients with angina (46.3%), exertional angina (27.7%), recent myocardial infarction (36.7%), healed myocardial infarction (34.1%), and especially in patients with rest angina (55.5%), but were relatively uncommon in patients with nonischemic heart disease (3.7%). The incidence of provoked coronary spasms in this study was 2.2-2.6 times higher than in previous reports with intravenous ER administration. More spasms were superimposed on significant atherosclerotic lesions than on nonfixed atherosclerotic lesions (42.8% vs 24.0%, p<0.01). No serious or irreversible complications were observed in this study. In conclusion, intracoronary administration of ER was a safe and reliable test. Compared with Caucasian patients, in Japanese patients, coronary arterial spasms occurred 2-3 times more frequently with various cardiac disorders.

Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations.

BackgroundThere are few reports regarding the concordance of coronary arterial response between acetylcholine (ACh) and ergonovine (ER) spasm provocation tests. ObjectivesWe attempted to perform selective spasm provocation tests to examine the incidence of provoked spasm in patients who had undergone first coronary angiography as much as possible and we compared the coronary arterial response and clinical usefulness between selective intracoronary injection of ACh and intracoronary administration of ER. MethodsWe performed 1508 selective spasm provocation tests, consisting of 873 ACh tests and 635 ER tests, from 1991 to 2002. We examined the frequency of provoked spasms of each agent retrospectively. ACh was injected in incremental doses of 20, 50 and 80u2009μg into the right coronary artery and 20, 50 and 100 μg into the left coronary artery. ER was administered as 10u2009μg/min over 4u2009min for a maximal dose of 40u2009μg in the right coronary artery and as 16u2009μg/min over 4u2009min for a total dose of 64u2009μg in the left coronary artery. Coronary spasm was defined as transient >99% luminal narrowing. ResultsIntracoronary ACh provoked spasms in 36.0% of patients and intracoronary ER induced spasms in 29.8% of patients. In patients with ischemic heart disease, the incidence of provoked spasms was not different between ACh tests (50.9%) and ER tests (43.8%). In contrast, the frequency of provoked spasms with ACh tests was significantly higher than that with ER tests (11.0% compared with 6.4%, P<0.05) in patients without ischemic heart disease. Moreover, ACh provoked more spasms in patients without fixed stenosis than ER (36.2% compared with 25.5%, P<0.01) and multiple spasms were frequently observed when performing ACh tests (40.0% compared with 27.0%, P<0.01). Major complications were observed in 1.4% of patients with ACh tests and in 0.2% of patients with ER tests. The need for intracoronary administration of isosorbide dinitrate to relieve coronary spasms during ER testing before performing another coronary artery test was more frequently observed in ACh tests (5.04% compared with 1.49%, P<0.01). However, no serious irreversible complications, such as death or acute myocardial infarction, were observed in this study. There was a significant difference in sex, history of smoking and hyperlipidemia between patients with and without spasms for both tests, whereas no difference in age or hypertension was observed in either test. ConclusionThus, both selective ACh and ER tests were useful as spasm provocation tests.

Detection of benzodiazepine receptor occupancy in the human brain by positron emission tomography

Benzodiazepine receptor occupancy in the brain following oral administration of clonazepam (CZP) with a dose of 30 μg/kg in six healthy young men and a further dose of 50 μg/kg in one of the subjects was estimated by carbon-11 labeled Ro15-1788 and positron emission tomography (PET). The effects of CZP on the latency of auditory event-related potentials (P300) were also studied. Overall brain 11C uptake was depressed and the % inhibition of 11C uptake in the gray matter of the brain at 30 min after [11C]Ro15-1788 injection was 15.3–23.5% (mean, n=6) following 30 μg/kg CZP when compared with that in the control experiment without any previous treatment. The 11C uptake in the cerebral cortex in the subject who received both doses decreased in a dose-related manner after 30 μg/kg and 50 μg/kg CZP. The P300 latency was prolonged significantly by 30 μg/kg CZP [31.6±16.3 ms (mean±SD, n=6), P<0.05]. The P300 latency in the same subject was prolonged in a dose-related manner by 30 μg/kg and 50 μg/kg CZP. The technique using [11C]Ro15-1788 and PET permits comparison of the pharmacological effects with the percentage of receptor sites which benzodiazepines occupy in the human brain. P300 also seems to be useful to investigate the pharmacological effects of benzodiazepines.

Quantitative in vivo analysis of benzodiazepine binding sites in the human brain using positron emission tomography

Central-type benzodiazepine binding sites were characterized in a single normal human subject, using positron emission tomography (PET) and the radiolabelled benzodiazepine antagonist, carbon-11 labelled flumazenil ([11C] Ro 15-1788). The subject was scanned using tracer alone and tracer plus 4 different concentrations of unlabelled Ro 15-1788, including one concentration of unlabelled Ro 15-1788, chosen to produce maximum displacement of [11C] Ro 15-1788 from specific binding sites. Concentrations of free, unmetabolized [11C] Ro 15-1788 in plasma were estimated using a simple extraction and ultrafiltration method. Radioactivity in the regional exchangeable pool in brain was estimated under non-saturation conditions from the ratio of radioactivity in brain to plasma, under saturation conditions and the kinetics of free ligand in plasma. The specific binding was, then, estimated by the difference between the total radioactivity in brain and exchangeable pool radioactivity. Scatchard analyses were performed to yield Bmax and Kd values under pseudo-equilibrium conditions, which was observed as an increase of specific binding/free with reduction in specific binding. In cerebral cortex and cerebellum, the Bmax values were about 62-73 nmol/l and the Kd values were 3.6-6 nM in the estimation of free ligand in plasma and 12-15 nM in the estimation of exchangeable pool in brain, as free in brain.

Clinical characteristics and possible mechanism of paroxysmal atrial fibrillation induced by intracoronary injection of acetylcholine

The results of this study demonstrate that diltiazem may reduce the recurrence rate of paroxysmal AF by 50%. Because the electrophysiologic effects of AF gradually resolve over a period of a few days,10 it is unlikely that episodes of paroxysmal AF that occur >4 to 5 days after a preceding episode can be attributed to the electrophysiologic effects of the previous episode. Therefore, diltiazem may be most likely to reduce the number of episodes of paroxysmal AF in patients who have only short periods of sinus rhythm between the episodes of AF.

Dopamine D2 and serotonin S2 receptors in susceptibility to methamphetamine psychosis detected by positron emission tomography

Positron emission tomography (PET) was used to assess the role of dopamine D2 receptors in the striatum and serotonin S2 receptors in the frontal cortex in the susceptibility to methamphetamine-induced psychosis. Subjects were six men who had previously experienced methamphetamine psychosis (methamphetamine subjects) and 10 age- and sex-matched control subjects. The radiotracer used was 11C-N-methylspiperone. Although binding availability, assessed by dynamic analysis, in the two regions did not differ between the two groups, the ratio of binding availability in the striatum to that in the frontal cortex significantly decreased in the methamphetamine subjects as compared with the control subjects. These findings suggest that an imbalance in the activity of these two receptors may be related to the susceptibility to methamphetamine psychosis.

Clinical and angiographical characteristics of acetylcholine- induced spasm: relationship to dose of intracoronary injection of acetylcholine.

ObjectivesThe purpose of this study was to clarify clinical and angiographical characteristics of acetylcholine (ACh)-induced spasm in the right and left coronary artery. Methods and resultsWe performed 557 consecutive procedures of spasm provocation tests of ACh from January 1991 to December 2000 in patients without significant stenosis. ACh was injected in incremental doses of 20, 50 and 80u2009μg into the right coronary artery and in incremental doses of 20, 50 and 100u2009μg into the left coronary artery if spasm had not been provoked. Coronary spasm was defined as positive with more than 99% transient luminal narrowing. Proximal spasm was defined as that of segments 1, 2, 5, 6, 7 and 11 and distal spasm as that of segments 3, 4, 8, 9, 12, 13 and 14. Low-ACh-dose-induced spasms showed the clinical findings and angiographical characteristics of higher incidence of variant angina, proximal spasms, focal spasms, more ST elevation and ischemic heart disease. In contrast, angiographical characteristics of high-Ach-dose-induced spasms were distal spasms and diffuse spasms and there was less variant angina and less ST elevation. ConclusionsLower ACh doses induced spasms more proximally and focally in the coronary artery, while higher doses of ACh provoked spasms more distally and diffusely.