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Biomedical subjects

S B Freedman

Publications and source records attributed to S B Freedman.

At least 73 records · Page 4Linked to original sources
PubMed1993

Asystole and bradycardia during dipyridamole stress testing in patients receiving beta blockers.

Only rarely have serious side effects been reported with the use of intravenous dipyridamole. We describe two cases of severe bradycardia, of which one led to asystole, in patients undergoing dipyridamole-thallium studies. The association between beta blocker therapy and the seven reported cases of asystole with dipyridamole is discussed and mechanisms postulated. Some caution is advised when patients on beta blockers or similar medications have dipyridamole-thallium studies.

Adrenergic beta-Antagonists↗
PubMed1993

Derivation and validation of a new angiographic score of right coronary artery perfusion.

A semi-quantitative right coronary artery score (RCA score) was derived from the ratio of the number of the major left ventricular branches of the right coronary artery to the total of the right coronary and left circumflex arteries, to stratify the extent of perfusion in patients with right coronary artery dominance. Thirty-seven patients with one-vessel coronary disease involving a dominant right coronary artery proximal to the left ventricular branches were selected for study. Thallium scintigraphy was performed after right intracoronary injection in 11 patients, and 26 patients underwent conventional stress thallium scintigraphy (24 exercise thallium and two dipyridamole thallium scintigraphy). Thallium scores of perfusion region size after right intracoronary thallium injection and perfusion defect size in stress thallium studies were quantitated from planar thallium images. Both the RCA score and the regional thallium scores spanned over a wide range. The RCA score (range 0.23-0.85) correlated best with the posterior (70 degrees left anterior oblique view) plus lateral segment (40 degrees left anterior oblique view) thallium score (r = 0.88 and 0.53 for intracoronary and stress thallium studies respectively). It also correlated with the summed thallium scores in the posterior, lateral, apical and inferior segments (r = 0.73 and 0.54 respectively) but not with thallium scores in the apex or inferior segment alone. The proposed RCA score quantitates the variable posterolateral perfusion territory of the right coronary artery, and could stratify the area of myocardium at risk from coronary stenosis in the majority of patients with right coronary dominance.

Angioplasty, Balloon, Coronary↗
PubMed1992

Stable expression of human D3 dopamine receptors in GH4C1 pituitary cells.

Human D3 dopamine receptor DNA was stably transfected into GH4C1 pituitary cells. Displacement of iodosulpiride binding in hD3 transfected cells (Kd = 0.3 nM, Bmax = 89 fmol/mg protein) by dopaminergic ligands was indistinguishable from that of hD3 receptors in CHO cells. Only two clonal cell lines exhibited weak GppNHp-dependent shifts in [3H]N-0437 binding, and these were used for functional assays. Neither arachidonic acid metabolism, cAMP levels, inositol phosphate turnover, intracellular calcium, or potassium currents were consistently affected by dopamine (1-10 microM). The paucity of responses indicates that human D3 receptors do not couple efficiently to these second messengers in GH4C1 cells.

Arachidonic Acids↗
PubMed1992

L-687,306: a functionally selective and potent muscarinic M1 receptor agonist.

The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist at guinea-pig cardiac M2 and ileal M3 muscarinic receptors. This compound gives an opportunity to study receptor reserve involved in muscarinic receptors in vitro and in vivo.

Animals↗
PubMed1992

Synthesis and in vitro biological profile of all four isomers of the potent muscarinic agonist 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane.

The four stereoisomers of the muscarinic agonist 7 have been synthesized from enantiomerically pure exo-azanorbornane esters (13a,b). The esters were obtained in optically active form by separation of the carboxamide diastereomers 12a,b, formed from the borane complex of exo-azanorbornane-3-carboxylate 10 and a chiral amine auxiliary. Using the known chirality of (R)-alpha-methylbenzylamine, an X-ray analysis was accomplished on 12a in order to determine the absolute configuration of the azanorbornane C4 chiral center. Each of the chiral esters 13a,b was separately transformed into the oxadiazoles with concomitant epimerization at C3 of the azanorbornane ring to afford the thermodynamic equilibrium mixture of isomers. Chromatographic separation followed by analysis of each isomer by NMR and GC allowed the absolute stereochemistry of all four isomers of 7 to be confirmed. Full biological evaluation in biochemical and pharmacological assays revealed that the 3R,4R isomer was the most active on receptor binding studies and the most potent on the pharmacological preparations, showing a 50-fold increase in potency at the M2 and M3 sites compared to M1.

Animals↗
PubMed1992

Synthesis and muscarinic activity of quinuclidinyl- and (1-azanorbornyl)pyrazine derivatives.

The synthesis and cortical muscarinic activity of a novel series of pyrazine-based agonists is described. Quinuclidine and azanorbornane derivatives were prepared either by reaction of lithiated pyrazines with azabicyclic ketones, followed by chlorination and reduction, or by reaction of the lithium enolate of the azabicyclic ester with 2-chloropyrazines followed by ester hydrolysis and decarboxylation. Substitution at all three positions of the heteroaromatic ring has been explored. Optimal muscarinic agonist activity was observed for unsubstituted pyrazines in the azanorbornane series. The exo-1-azanorbornane 18a is one of the most efficacious and potent centrally active muscarinic agonists known. Studies on the 3-substituted derivatives have provided evidence of the preferred conformation of these ligands for optimal muscarinic activity. Substitution at C6 gave ligands with increased affinity and reduced efficacy. Moving the position of the diazine ring nitrogens to give pyrimidine and pyridazine derivatives resulted in a significant loss of muscarinic activity.

Animals↗
PubMed1992

Efficacy, safety and duration of nitrate-free interval to prevent tolerance to transdermal nitroglycerin in effort angina.

The magnitude of tolerance to the anti-anginal efficacy of transdermal nitroglycerin and the efficacy and safety of short (4 h) and long (10 h) nitrate-free intervals for its prevention, were investigated in a randomized, double-blind, placebo-controlled crossover trial of 4 week-long treatment regimens: placebo, continuous therapy with a 50 mg patch (10 mg.24 h-1), and 4 h and 10 h nitrate-free periods. Only patients showing greater than 1 min increase in time to 1 mm ST depression after acute patch administration were eligible. Twelve men completed the study. One other anti-anginal medication (a beta-blocker in nine and calcium antagonist in two) was permitted in a constant dose throughout the study. Patients underwent exercise testing on days 1 and 7 of each treatment period, and 24 h ambulatory ECG monitoring on day 6. Compared to placebo, transdermal nitroglycerin on day 1 significantly improved time to 1 mm ST depression by 35%, and time to angina, exercise duration and maximal workload by 21%, 13% and 9% respectively. These improvements were totally lost after 7 days' continuous therapy, but completely maintained by a 10 h nitrate-free period (improvements of 35%, 25%, 16% and 11% respectively) but not by a 4 h nitrate-free period (non-significant improvements of 15%, 2%, 4% and 1% respectively). The differences between 10 and 4 h nitrate-free were significant for each end-point. Neither duration of ambulatory ischaemia, nor the proportion of patients experiencing greater than or equal to 5 min ischaemia during the scheduled nitrate-free interval differed between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1992

L-689,660, a novel cholinomimetic with functional selectivity for M1 and M3 muscarinic receptors.

1. L-689,660, 1-azabicyclo[2.2.2]octane, 3-(6-chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (pKD (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L-689,660 had a low ratio (34) of pKD (apparent) values for the displacement of binding of the antagonist ([3H]-N-methylscopolamine ([3H]-NMS) compared with the displacement of the agonist [3H]-oxotremorine-M ([3H]-Oxo-M), in rat cerebral cortex. Low NMS/Oxo-M ratios have been shown previously to be a characteristic of compounds that are low efficacy partial agonists with respect to stimulation of phosphatidyl inositol turnover in the cerebral cortex. 2. L-689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M1 muscarinic receptors in the rat superior cervical ganglion, L-689,660 was a potent (pEC50 7.3 +/- 0.2) full agonist in comparison with (+/-)-muscarine. At M3 receptors in the guinea-pig ileum myenteric plexus-longitudinal muscle or in trachea, L-689,660 was again a potent agonist (pEC50 7.5 +/- 0.2 and 7.7 +/- 0.3 respectively) but had a lower maximum response than carbachol. In contrast L-689,660 was an antagonist at M2 receptors in guinea-pig atria (pA2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices. 3. The putative M1-selective muscarinic agonist, AF102B (cis-2-methylspiro-(1,3-oxathiolane 5,3')-quinuclidine hydrochloride) was found to have a profile similar to L-689,660 but had up to 100 times less affinity in binding and functional assays.RS-86 (2-ethyl-8-methyl-2,8-diazospiro[4,5]decan 1,3-dionehydrochloride) also had lower affinity than L-689,660, and had no binding selectivity for muscarinic receptor subtypes. RS-86 had a higher NMS/Oxo-M ratio than L-689,660 and was a full agonist at MI,M2 and M3 receptors in the functional pharmacological assays.4. The functional selectivity of L-689,660 in muscarinic pharmacological assays is consistent with the effects of a low efficacy partial agonist in tissues with different effective receptor reserves.

Animals↗
PubMed1991

The unstable ST segment early after thrombolysis for acute infarction and its usefulness as a marker of recurrent coronary occlusion.

To investigate the incidence of early recurrent ST elevation after intravenous thrombolytic therapy for acute myocardial infarction, 12-lead electrocardiograms were continuously monitored for 571 +/- 326 minutes in 31 patients presenting within 4 hours of symptom onset. The study group comprised 9 women and 22 men (mean age +/- standard deviation 53 +/- 12 years), with ST elevation (anterior in 15, inferior in 16) on the initial electrocardiogram, who were given either tissue plasminogen activator (22 patients) or streptokinase (9 patients). Angiography was performed in 30 of 31 patients at 7 to 10 days. Early (less than 3 hours) resolution of ST elevation occurred in 19 patients (61%) at a median of 94 minutes (interquartile range 57 to 113) after thrombolysis, whereas 12 (39%) had no or late (greater than 6 hours) resolution. Eleven of the 19 with early resolution (58%) had either transient (5 patients) or sustained (6 patients) recurrences of ST elevation. Recurrent ST elevation was equal to or more than the initial peak elevation in 9 of 11 patients, and greater than 75% of initial peak in 2. A total of 25 episodes of recurrent ST elevation were observed in the 11 patients (19 transient and 6 sustained episodes), of which 8 (32%) were silent. The proportion of silent episodes was similar for transient (35%) and sustained (33%) recurrences. All patients with sustained recurrent ST elevation had at least 1 preceding transient recurrence. The median duration of transient recurrent ST elevation was 43 minutes (28 to 63).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Angiography↗
PubMed1991

Prognostic significance of a predischarge exercise test in risk stratification after unstable angina pectoris.

The prognostic significance of exercise testing was compared with clinical and electrocardiographic (ECG) variables in a prospective study of 107 patients with unstable angina discharged from the hospital on medical therapy. During a follow-up period of 12.8 +/- 1.4 months, 10 patients (9%) had a nonfatal myocardial infarction (n = 8) or died (n = 2) and 22 (20%) were readmitted with recurrent unstable angina. The relation between 20 clinical, ECG and exercise test variables and the risk of adverse outcome (death, nonfatal myocardial infarction or recurrent unstable angina) was analyzed using both univariate and multivariate (logistic regression) analysis. Univariate predictors of adverse outcome included diabetes mellitus, evolutionary T wave changes, T wave changes on the preexercise ECG and low maximal rate-pressure product during exercise. Independent predictors of adverse outcome in multivariate analysis included diabetes mellitus, evolutionary T wave changes after admission, rest pain during hospitalization, ST depression during exercise and low maximal rate-pressure product. A predictive model constructed using the regression equation and all independent predictors stratified patients into high and low risk groups (41% and 5% risk of adverse outcome, respectively). The result of a predischarge exercise test adds independent prognostic information to clinical and ECG data in medically treated patients with unstable angina and could be used in combination with clinical and ECG data to identify patients at risk of adverse events.

Angina, Unstable↗
PubMed1991

Tetrahydropyridyloxadiazoles: semirigid muscarinic ligands.

Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.

Animals↗
PubMed1990

In vivo characterisation of novel efficacious muscarinic receptor agonists.

Although a number of muscarinic agonists have been used in clinical trials for Alzheimer's Disease, many of these compounds are low in potency and have only limited intrinsic efficacy. The present study describes four non-quaternary oxadiazole based muscarinic agonists from a quinuclidine and a 1-azanorbornane series. These displayed up to 1000 fold higher affinity than arecoline and were efficacious muscarinic agonists at cortical receptors. All four compounds produced peripherally mediated salivation and centrally mediated hypothermia at doses 50-50,000 fold lower than arecoline. The most potent was L-670,548, the methyl oxadiazole in the 1-azanorbornane series, which had an ED50 of 0.0016 mg/kg on the hypothermia model. This derivative was also the most potent compound in ex vivo binding studies (ED50 0.0069 mg/kg) and showed excellent brain penetration (3.8% of the administered dose). These derivatives are the first non quaternary efficacious agonists which show good penetration into the CNS (central nervous system), and will prove useful tools in understanding the role of muscarinic receptors in CNS function.

Animals↗
PubMed1990

Effects of diltiazem and long-term beta 1-adrenergic blockade on hemodynamics and blood flow during exercise in patients with stable angina pectoris.

The short-term effects of oral diltiazem on hemodynamics and distribution of cardiac output at rest and during semiupright bicycle exercise were evaluated in eight patients with stable effort angina on long-term beta 1-adrenergic blockade. Cardiac output and iliofemoral blood flow were measured using thermodilution. The patients were exercised to the same work load on a bicycle before and 2 h after oral diltiazem (60 mg in two patients and 120 mg in six). At maximal exercise, diltiazem reduced heart rate from 94 +/- 5 to 88 +/- 6 beats/min (p less than 0.01), mean arterial pressure from 139 +/- 5 to 127 +/- 4 mm Hg (p less than 0.01) and systemic vascular resistance from 9.7 +/- 0.7 to 8.4 +/- 0.4 x 10(2) dynes.s.cm-5 (p less than 0.05) compared with control. During exercise, cardiac output, iliofemoral blood flow, mean pulmonary wedge pressure and mean right atrial pressure were not altered, but stroke volume increased from 119 +/- 11 to 131 +/- 10 ml (p less than 0.05). Maximal ST segment depression during exercise was decreased and angina was less. Diltiazem does not alter the distribution of the cardiac output during exercise but improves ischemia.

Adrenergic beta-Antagonists↗
PubMed1990

A new method of scoring coronary angiograms to reflect extent of coronary atherosclerosis and improve correlation with major risk factors.

We developed a new angiographic score of the extent of coronary disease (extent score), which we compared with conventional stenosis and vessel scores that emphasize the severity of stenosis. Scores were determined in 132 patients (29 women, 103 men with a mean age of 55 +/- 10 years) who underwent elective coronary angiography. Risk factors were more closely related to the extent score than to either the stenosis or vessel scores (Total R2 = 0.35 versus 0.28 (p less than 0.001) and 0.25 (p less than 0.001), respectively). The extent score was more closely related to age (r = 0.30, p less than 0.05), than was either stenosis (r = 0.21 ns) or vessel score (r = 0.26, p less than 0.05). Apolipoprotein B was the strongest predictor of both extent and stenosis scores but was more closely related to the extent score (r = 0.36, p less than 0.05), even after correction for age and gender. This new angiographic score that assesses the extent of coronary disease is simple to perform and correlates better with age and lipoprotein risk factors than conventional scores do.

Adrenergic beta-Antagonists↗
PubMed1990

Novel quinuclidine-based ligands for the muscarinic cholinergic receptor.

Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous system and which are capable of displaying high efficacy at cortical sites. With use of a biochemical assay capable of measuring receptor affinity and predicting cortical efficacy, it has been discovered that an oxadiazole ring and related heterocycles can function as bioisosteric replacements for the ester moiety found in several known muscarinic ligands. Within this series there exist compounds which span the efficacy range from high-efficacy agonist through partial agonists to antagonists with affinity comparable or superior to that of classical quaternary ammonium ligands. Consistent with recent molecular biology studies, structure-activity trends are interpreted in terms of separate binding sites for agonists and antagonists with H-bonding interactions characterizing agonist behavior and lipophilic binding characterizing antagonist behavior. Thus the aminooxadiazole moiety has structural features which are optimized for an agonist profile.

Animals↗
PubMed1990

Synthesis and muscarinic activities of 1,2,4-thiadiazoles.

A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.

Animals↗