Search PubMed⌕ Search

Biomedical subjects

S B Freedman

Publications and source records attributed to S B Freedman.

At least 37 records · Page 2Linked to original sources
PubMed1997

4-Heterocyclylpiperidines as selective high-affinity ligands at the human dopamine D4 receptor.

5-(4-Chlorophenyl)-3-(1-(4-chlorobenzyl)piperidin-4-yl)pyrazole (3) was identified from screening of the Merck sample collection as a human dopamine D4 (hD4) receptor ligand with moderate affinity (61 nM) and 4-fold selectivity over human D2 (hD2) receptors. Four separate parts of the molecule have been examined systematically to explore structure-activity relationships with respect to hD4 affinity and selectivity over other dopamine receptors. It was found that the 4-chlorophenyl group attached to the pyrazole is optimal, as is the 4-substituted piperidine. The lipophilic group on the basic nitrogen is more amenable to change, with the optimal group found to be a phenethyl. The aromatic heterocyle can be altered to a number of different groups, with isoxazoles and pyrimidines showing improved affinities. This heterocycle can also be advantageously alkylated, improving the selectivity of the compounds over D2 receptors. It is hypothesized that the conformation around the bond joining the aromatic heterocycle to the piperidine is important for D4 affinity, based on crystal structures of isoxazoles (29 and 30) and on a conformationally constrained compound (28). Putting all the favorable changes together led to the discovery that 5-(4-chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)iso xazole (36) is a nanomolar antagonist at human dopamine D4 receptors with > 500-fold selectivity over hD2 and > 200-fold selectivity over hD3. Compound 36 is an antagonist of hD4 receptors with good oral bioavailability of 38%, a half life of 2 h, and brain levels 10-fold higher than plasma levels.

Cell Line↗
PubMed1997

Usefulness of laboratory mental stress test in patients with stable coronary artery disease.

BACKGROUND AND HYPOTHESIS: Many episodes of ischemia in daily life are silent occurring during sedentary activities and may be related to mental stress. In 35 patients with stable angina and positive exercise test awaiting bypass surgery, we investigated whether laboratory mental stress tests would trigger ischemia of a comparable severity to that occurring in daily life and attempted to elucidate some of the underlying mechanisms. METHODS: All patients underwent exercise testing, personality assessment, 2-day Holter monitoring, and laboratory mental stress tests while on their usual medications. RESULTS: Only four patients (12%) had positive mental stress test (ST depression > or = 0.1 mV). All episodes were silent and usually associated with fast heart rate (> 90 beats/min). In contrast, ambulatory ischemia was common (average duration of 51 min per 24 h), and at least one episode was recorded in 27 patients (77%) including the 4 with positive test. Patients with positive mental stress test had a higher heart rate during testing (124 +/- 24 vs. 86 +/- 16 beats/min, p < 0.01), and a shorter exercise time and time to 1 mm ST depression on cycle ergometry than those with negative mental stress test. None of the four patients were on beta blockers. There was no difference in personality inventory between the two groups. Comparisons between patients with and without positive mental stress test revealed no difference in the duration and frequency of ambulatory ischemia, or in the occurrence of silent ischemia. However, the heart rate at onset of ambulatory ischemia tended to be higher in the patients with positive mental stress test (96 +/- 9 vs. 62 +/- 43, p = 0.07). Further subgroup analysis in patients without beta blockers (4 mental stress test positive and 18 negative) showed similar results. CONCLUSIONS: Laboratory mental stress test is a weak inducer of ischemia detected by electrocardiographic monitoring in patients with frequent ambulatory ischemia. Wall motion evaluation during mental stress test may improve sensitivity. While larger scale studies may determine its clinical role, the present study illustrated that patients with heightened heart rate response to mental stress were identified in whom beta blockers could be the drug of choice.

Activities of Daily Living↗
PubMed1997

L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests.

This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.

Amphetamine↗
PubMed1996

Angiographic severity of coronary narrowing is a surrogate marker for the extent of coronary atherosclerosis.

Most acute coronary events occur because of narrowings at sites of angiographically minor plaque. Despite this, angiograms are reported in terms of the number of coronary arteries with severe narrowings. Disease severity is correlated with prognosis, but this may simply be due to a strong positive correlation between the severity and extent of coronary atheroma. We therefore aimed to assess the relation between the severity and the extent of coronary atherosclerosis. Coronary angiograms of 350 consecutive patients referred for elective cardiac catheterization were analyzed. Two independent observers calculated the number of arteries with > or = 70% stenosis, a disease severity score, and an extent score (percentage of the coronary artery length with any luminal irregularity). There were no obstructive stenoses in 123 patients (35%); 91 (26%) had 1-vessel disease, 81 (23%) had 2-vessel disease, and 55 (16%) had 3-vessel coronary artery disease. The median severity score was 1 (lower, upper quartile 0, 3; range 0 to 8), and the median extent score was 66% (lower, upper quartile 32, 83; range 0% to 100%). There was a strong linear relation between severity score and extent score (r = 0.62, p < 0.001); however, the data were better described by 2 intersecting straight lines, with a steeper increase in disease severity when the extent score was between 80% and 90% (F1;121 = 6.9, p = 0.001). The severity of coronary disease is therefore significantly correlated with disease extent. This may explain the observed relation between the number of arteries with obstructive stenoses and subsequent risk, even though most events occur at sites of minor plaque.

Adult↗
PubMed1996

Are radioligand antagonist/agonist binding ratios in rat pancreas predictive of functional efficacy of cholecystokinin receptor agonists and antagonists?

Radioligand binding assays have been previously used to predict the relative efficacy of novel ligands. In the present study we have investigated whether for the cholecystokinin CCK-A receptors in the rat pancreas, the ratio of binding affinities for compounds for antagonist and agonist radioligands are predictive of functional activity. A number of classical cholecystokinin agonists, such as CCK-8S, caerulein, CCK-8DS, pentagastrin and CCK-4 had antagonist/agonist binding ratios of 4-fold or greater. All compounds behaved as full agonists in the stimulation of phosphatidylinositol (PI) turnover and increase in amylase secretion in rat pancreas. In contrast, compounds such as the benzodiazepine derivatives devazepide and L-365,260 had binding ratios of less than one and lacked agonist activity in either functional assay. Interestingly, the dipeptide derivative CI-988, which has been described as a selective CCK-B antagonist, was found to have an antagonist/agonist binding ratio of 1.5 for the CCK-A receptors in rat pancreas which was sufficiently high for this compound to behave as a full agonist in the amylase assay, although CI-988 did not exhibit agonist activity in the PI assay. These results suggest that the effective receptor reserve in the amylase assay is greater than that required to stimulate PI turnover, and that the selective peptoid CCK-B antagonist CI-988 has weak agonist activity at CCK-A receptors.

Animals↗
PubMed1996

Correlation between post-ejection shortening and improvement in regional wall motion after revascularization in patients with coronary artery disease.

This study investigates the relationship between regional post-ejection shortening and improvement in wall motion after revascularization in patients with severe regional left ventricular contractile dysfunction. Canine studies have documented the phenomenon of post-systolic shortening during acute ischemia, and this predicted recovery of contractile function when ischemia was relieved. This delayed shortening from the ischemic segment would cause regional emptying while the other normal portion of the left ventricle starts to have diastolic relaxation. This was detectable by standard phase analysis of the radionuclide ventriculogram, the abnormal region with delayed emptying being distinguished from the normal portion of left ventricle as an area with a homogeneous phase delay. Twelve patients with successful revascularization and a pre-operative study demonstrating a single homogeneous area of phase delay were identified. The area was demarcated and the regional volume-time curve constructed. The volume-time curve of the abnormal region is analogous to the myocardial segment length versus time relationship in the canine model. We quantitated the amount of delayed (post-systolic) emptying in the demarcated region as the difference between end-systole counts and post-systolic nadir counts, and this was normalised to left ventricular stroke count. After revascularization, regional ejection fraction improved from 44 +/- 10% to 62 +/- 14% (P < 0.001), representing a 47 +/- 50% improvement over baseline. The percentage improvement in regional ejection fraction correlated with post-systolic emptying (r = 0.74, P < 0.05) but not with initial regional ejection fraction. In conclusion, post-ejection shortening causes regional post-systolic emptying and this correlates with post-revascularization improvement in regional wall motion.

Adult↗
PubMed1996

Electrocardiographic identification of the infarct-related artery in acute inferior myocardial infarction.

Differentiation between left circumflex occlusion and right coronary occlusion in inferior acute myocardial infarction is a common clinical problem. This study investigated new electrocardiographic markers for differentiation, including T wave inversion, and individual inferior and precordial lead ST level, versus the traditional criterion of lateral ST elevation. In 95 angiographically characterised patients, ST elevation in lateral chest lead V5 or V6 had a sensitivity of 56% and specificity of 92% to predict left circumflex related acute myocardial infarction while the absence of lateral T inversion in I and AVL was even more sensitive (89%) though less specific (74%). A criterion of ST depression in V1 > 0.1 mV has a sensitivity of 61% and specificity of 84% whereas a criterion of ST level in III minus II < or = 0.1 mV has a sensitivity of 94% and specificity of 37% in predicting left circumflex related acute myocardial infarction. These criteria were then tested in another 49 patients subsequently recruited with inferior acute myocardial infarction. Useful parameters that discriminated left circumflex related acute myocardial infarction from right coronary related acute myocardial infarction include lateral ST elevation (38% vs. 7%, P < 0.05), absence of lateral T inversion (50% vs. 15%, P < 0.05), and ST depression in V1 of more than 0.1 mV (50% vs. 7%, P < 0.05). The present study revealed new electrocardiographic clues to suggest a left circumflex related inferior acute myocardial infarction other than lateral ST elevation. However, it should be noted that no single electrocardiographic variable or their combinations could identify the infarct-related artery with complete certainty.

Coronary Vessels↗
PubMed1996

Electrocardiographic measurement of infarct size after thrombolytic therapy.

OBJECTIVES: We examined the utility of the 32-point QRS score from the 12-lead electrocardiogram (ECG) for measurement of the ischemic risk region and infarct size in patients receiving thrombolytic therapy. BACKGROUND: The QRS score offers a means of evaluating the therapeutic benefit of thrombolytic therapy by comparing final infarct size with the initial extent of ischemic myocardium. METHODS: The study included 38 patients (34 men, 4 women; mean [+/-SD] age 54 +/- 10 years) with a first infarction (18 anterior, 20 inferior). The maximal potential QRS score (QRS0) was assigned to all leads with >/= 100-microV ST elevation on the initial ECG. The QRS scores were calculated at 7 and 30 days after infarction. Left ventricular ejection fraction was measured by radionuclide ventriculography at 1 month. Twenty-eight patients had thallium (Tl)-201 and technetium (Tc)-99m pyrophosphate tomographic measurement of the ischemic region and infarct size. RESULTS: The QRS0 was 10.3 +/- 3.1 (mean +/- SD) for anterior and 10.4 +/- 3.5 for inferior infarcts. The QRS scores were similar at 7 and 30 days for both anterior (5.6 +/- 3.4 vs. 5.5 +/- 3.4) and inferior infarcts (3.7 +/- 2.6 vs. 2.9 +/- 2.2). The day 7 QRS score and ejection fraction at 1 month were inversely correlated (r = -0.74, p < 0.01). The Tl-201 perfusion defect was 34 +/- 11% of the left ventricle for anterior and 32 +/- 7% for inferior infarcts. Subsequent Tc-99m pyrophosphate infarct size was 15 +/- 9% of the left ventricle for anterior and 17 +/- 9% for inferior infarcts. The QRS0 was correlated with the extent of the Tl-201 perfusion defect (r = 0.79, p < 0.001), and the day 7 QRS score was correlated with Tc-99m pyrophosphate infarct size (r = 0.79, p < 0.005). CONCLUSIONS: The 32-point QRS score can provide useful immediate measurements of the ischemic risk region and subsequent infarct size.

Aged↗
PubMed1996

CCK-B receptor-mediated stimulation of polyphosphoinositide turnover in GH3 pituitary cells in response to cholecystokinin and pentagastrin.

CCK-B receptor-mediated polyphosphoinositide (PPI) turnover in GH3 pituitary cells has been examined and comparisons are made with Ca2+ mobilisation and receptor binding data, previously described. Sulphated cholecystokinin octapeptide (CCK-8s) and the CCK-B-selective agonist pentagastrin dose-dependently stimulated PPI turnover in GH3 cells with similar maximal increases of 3.0 fold and 3.3 fold, respectively, in production of [3H]inositol phosphates over control. Responses, measured over 30min periods in the presence of 10mM LiCl, were generally maximal for both agonists at 100nM. Consistent with their [125]Bolton Hunter CCK-8s (BHCCK) binding affinities and with effects on Ca2+ mobilisation, CCK-8s was slightly more potent than pentagastrin in stimulating PPI turnover (EC50s 1.3nM and 3.9nM respectively). Both peptides showed higher potency in the PPI assay than in Ca2+ studies. 100nM pentagastrin-induced PPI turnover was dose-dependently inhibited by the CCK-B receptor-selective antagonist L-365,260 (IC50 470nM) whilst the CCK-A receptor antagonist, devazepide, only produced weak partial inhibition (18% at 10,000nM). Antagonists alone were observed to depress control activity in PPI turnover but not in Ca2+ mobilisation assays. The selectivity of L-365,260 compared to devazepide was similar in binding studies to that for both 100nM pentagastrin-induced functional responses. Schild analysis of antagonism of PPI turnover by L-365,260 yielded a line with slope close to unity (1.07) and a pKB of 8.27+/-0.05.

Animals↗
PubMed1996

Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor.

We identified a novel azaindole derivative, L-750,667, that has high affinity (Ki = 0.51 nM) and >2000-fold selectivity for D4 dopamine receptors compared with its activity at D2 and D3 dopamine receptors. L-750,667 had little affinity for rat D1/D5 dopamine receptors, sigma binding sites, or 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptors. In functional studies, L-750,667 exhibited high affinity antagonist activity at D4 receptors, reversing dopamine (1 microM)-induced inhibition of cAMP accumulation in human embryonic kidney (HEK) cells expressing the human D4 receptor (hD4 HEK) with an EC50 value of 80 nM. The radioiodinated form of L-750,667 bound specifically to the human dopamine D4 receptor expressed in HEK cells and saturation analysis revealed a single high affinity binding site for [125I]L-750,667 (Kd = 0.16 +/- 0.06 nM). The maximum number of binding sites (Bmax) estimated using [125I]L-750,667 in hD4 HEK cells was 251 +/- 71 fmol/mg, which correlated well with the Bmax value determined using [3H]spiperone (227 +/- 83 fmol/mg) in the same membrane preparations. The pharmacological profile of [125I]L-750,667 binding to hD4 HEK cells was evaluated using known dopamine receptor agonists and antagonists. The rank order of potencies for dopamine receptor agonists was dopamine > quinpirole > 6,7-aminodihydroxytetralin > 5,6-aminodihydroxytetralin. Dopamine receptor antagonists also showed high affinity, with a rank order of haloperidol > chlorpromazine > domperidone > (+)-butaclamol > (-)-sulpiride = (+)-sulpiride > (+)-SCH23390 > (-)-butaclamol. [125I]L-750,667, bound to D4 receptors in a stereoselective manner with (+)-butaclamol showing higher activity than its respective enantiomer (-)-butaclamol. These results show that [125I]L-750,667 is a novel, highly selective radioligand for dopamine D4 receptors and may be used to investigate the dopamine D4 receptor population in the central nervous system.

Animals↗
PubMed1995

Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease.

BACKGROUND: Intima-media thickness (IMT) of the common carotid artery (CCA), measured with external vascular ultrasound, has been widely used in clinical trials as a surrogate marker for coronary atherosclerosis. Despite this, the degree of correlation between carotid IMT and the extent and severity of coronary artery disease (CAD) is not known. METHODS AND RESULTS: Common carotid IMT was measured by ultrasound in 350 consecutive subjects of age 60 +/- 10 years (range, 30 to 85 years) on the day of coronary angiography. Carotid mean IMT was 0.83 +/- 0.20 mm (range, 0.43 to 1.80 mm), and maximum IMT was 1.04 +/- 0.27 mm (range, 0.49 to 2.19 mm). Coronary angiograms were analyzed by independent observers for disease severity (number of vessels with > or = 70% stenosis), extent score, and a modified Gensini score. Mean carotid IMT was weakly but significantly correlated with CAD severity (r = .26), extent (r = .23), and modified Gensini score (r = .29, P < .0001 for all correlations). Carotid IMT was not clinically useful, however, because it was not specific or sensitive enough to identify patients with or without significant CAD. Increasing age, male sex, and presence of diabetes were all associated with a significantly (P < .01) higher CAD score than the average for any level of carotid IMT, suggesting differential effects of these traditional risk factors on the coronary and common carotid arteries. CONCLUSIONS: Although carotid IMT is significantly correlated with extent and severity of CAD, the relationship is weak. This relatively poor correlation (r2 < .10) should be considered in the interpretation of clinical trials that use carotid IMT as a surrogate end point for coronary atherosclerosis.

Cardiac Catheterization↗
PubMed1995

Relation between ischemia time, infarct size, and left ventricular function in humans.

BACKGROUND: Experimental studies indicate that duration of ischemia is a major determinant of myocardial infarct size, but only limited information is available about the relation between ischemia time and infarct size in individual patients. This prospective study sought to document the role of ischemia time as a determinant of infarct size in humans. METHODS AND RESULTS: We studied 61 patients (50 men, 11 women) 57 +/- 11 years old admitted with a first infarct (31 anterior, 30 inferior) who underwent continuous 12-lead ECG monitoring to document ischemia time. Infarct size (32-point QRS score on day 7) and changes in regional myocardial wall motion (echocardiography) during the following month were related to ischemia time. Among patients with < 3 hours of ischemia (n = 16), mean infarct size on day 7 was 21 +/- 13% of potential infarct size; in patients with 3 to 6 hours of ischemia (n = 23), infarct size was 38 +/- 18% of potential (P < .05 versus 0 to 3 hours of ischemia); and in patients with 6 to 9 hours of ischemia (n = 10), infarct size was 66 +/- 14% of potential (P < .05 versus 3 to 6 hours). In contrast, the 12 patients with an ischemia time > 9 hours had a final infarct size of 77 +/- 10% of potential (P < .01 versus 3 to 6 hours). Multivariate regression identified size of risk region, duration of ischemia, and degree of initial ST-segment elevation as independent predictors of infarct size, of which the most important variable was ischemia time. The regression models accurately predicted both individual absolute infarct size (R2 = .83) and individual infarct/risk ratio (R2 = .74). Patients with < 6 hours of ischemia exhibited significant recovery of myocardial wall motion by day 7 (wall motion score, 2.1 +/- 1.4 versus 5.7 +/- 3.2 on day 1, P < .01). Patients with 6 to 9 hours of ischemia had some recovery by 1 month (score, 6.3 +/- 4.4 versus 10.9 +/- 3.8 on day 1, P < .01), but patients with > 9 hours of ischemia had little recovery of wall motion by 1 month (score, 10.3 +/- 4.5 versus 12.8 +/- 3.1 on day 1, P < .05). CONCLUSIONS: Measurement of ischemia time allows improved prediction of infarct size in humans. Significant myocardial salvage and functional recovery may be achieved by reperfusion up to 9 hours after coronary occlusion. Continuous ST-segment monitoring should be used to measure ischemia time and guide interventions to reperfuse the infarct artery.

Adult↗
PubMed1995

Intermittent transdermal nitrates do not improve ischemia in patients taking beta-blockers or calcium antagonists: potential role of rebound ischemia during the nitrate-free period.

OBJECTIVES: This study was conducted to determine whether rebound ischemia occurs during nitrate-free periods with intermittent cutaneous nitroglycerin therapy in patients with angina pectoris who are receiving background antianginal therapy. BACKGROUND: Rebound angina has been suggested to be a complication of the nitrate-free period with long-term cutaneous nitroglycerin therapy given intermittently to prevent tolerance. METHODS: Fifty-two patients with stable effort angina taking either a beta-adrenergic blocking agent (n = 25) or diltiazem (n = 22) or their combination (n = 5) completed a randomized, double-blind, placebo-controlled crossover study of cutaneous nitroglycerin patches (50 mg). Active or placebo patches were worn for 1 week, applied at 8 AM and removed at 10 PM to provide a 10-h daily nitrate-free (or placebo-free) period. During the last 48 h of each study phase, a Holter monitor was used to detect ischemia. RESULTS: Only 31 patients experienced ischemia during either phase of the study (23 during the patch-off period). A total of 463 ischemic episodes were recorded: 246 during placebo and 217 during nitroglycerin (p = 0.8, for per patient comparison). The majority (88%) of ischemic episodes were silent. Mean (+/- SEM) duration of ischemia during the total 48-h period was similar during active and placebo phases (35.5 +/- 15.0 min/24 h for active therapy vs. 29.7 +/- 9.8 for placebo, p = 0.8). This was due to an increase in duration of ischemia with active therapy during the patch-off period (46.9 +/- 17.9 min/24 h for active therapy vs. 22.5 +/- 9.2 for placebo, p = 0.07) and a decrease during the patch-on period (27.5 +/- 14.0 min/24 h for active therapy vs. 34.5 +/- 11.0 min/24 h for placebo, p = 0.16). The pattern of diurnal distribution of ischemic episodes differed between active and placebo phases. During placebo there was a nadir in the incidence of ischemia in the overnight patch-off period, with a significantly lower incidence between midnight and 6 AM (25 episodes) compared with the mean number of episodes during the three other 6-h periods (73 episodes, p < 0.001). During the nitroglycerin patch-off period, there was a loss of this overnight nadir, with the same incidence of ischemia between midnight and 6 AM (53 episodes) as the mean number of episodes for the three other 6-h periods (54 episodes). CONCLUSIONS: The majority of patients taking background antianginal therapy experienced no ischemia during the patch-off period. In the 44% of patients with ischemia during this period, there was a nonsignificant increase in the duration of ischemia with active therapy. Although this result was statistically inconclusive, the change in the distribution of diurnal ischemia offers suggestive evidence that rebound ischemia may be a problem with regard to intermittent cutaneous nitroglycerin.

Administration, Cutaneous↗