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Biomedical subjects

F Cassidy

Publications and source records attributed to F Cassidy.

At least 37 records · Page 2Linked to original sources
PubMed1998

Familial leukoencephalopathy in bipolar disorder.

OBJECTIVE: Imaging studies of patients with bipolar disorder demonstrate changes in deep white matter and subcortical gray nuclei that are seen as focal hyperintensities on T2-weighted magnetic resonance imaging (MRI). The objective of this study was to examine MRIs in a family with a strong history of bipolar disorder to look for possible MRI abnormalities in members with and without affective illness. METHOD: The authors obtained MRIs of 21 members of a family with a strong history of bipolar disorder. Eight of the family members studied had bipolar illness, one had symptoms of bipolar disorder but did not meet full DSM-III-R criteria, two had unipolar disorder, and 10 did not have bipolar disorder. RESULTS: Fifteen of the 21 family members had MRI findings, including six of 10 family members who had no affective disorder and all of those with bipolar disorder. Lesions of both white matter and subcortical gray nuclei were found. CONCLUSIONS: Although the clinical significance of these MRI findings is unknown, the high prevalence of MRI findings in both affected and unaffected family members suggests that MRI findings may potentially serve as a biological marker for bipolar disorder. Recent genetic studies have established a link between familial leukoencephalopathy and chromosome 19. If leukoencephalopathy appears to be related to bipolar disorder, it may allow clearer characterization of the genetics of the disorder.

Adolescent↗
PubMed1997

Design of [R-(Z)]-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitri le (SB 202026), a functionally selective azabicyclic muscarinic M1 agonist incorporating the N-methoxy imidoyl nitrile group as a novel ester bioisostere.

Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

Alzheimer Disease↗
PubMed1997

The performance of DSM-III-R major depression criteria in the diagnosis of bipolar mixed states.

Two hundred thirty-seven (237) manic patients diagnosed by DSM-III-R criteria as either purely manic (204) or mixed bipolar (33) were reviewed for analysis of the diagnostic performance of the DSM-III-R criteria required to diagnose the mixed bipolar state. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic efficiency of each of the 9 DSM-III-R criteria for major depression in this cohort. As predicted, four of the major depression criteria had low diagnostic utility, with PPV's less than 0.3. Those items were: weight change; sleep disturbance; psychomotor change; and diminished ability to think or concentrate or indecisiveness. Four symptoms: anhedonia, fatigue, feelings of worthlessness or guilt, and recurrent thoughts of death or suicidal ideation had acceptable utility for the diagnosis of mixed states.

Adolescent↗
PubMed1997

Lack of relapse with tryptophan depletion following successful treatment with ECT.

OBJECTIVE: Although the antidepressant mechanism of ECT is unknown, there are considerable data to support serotonergic involvement. The effects of tryptophan depletion were studied in patients with major depression treated successfully with ECT. METHOD: Five patients who had been successfully treated with ECT for major depression were studied in a randomized, double-blind, crossover design comparing tryptophan depletion to a placebo procedure. RESULTS: No effect of tryptophan depletion on mood symptoms was observed despite more than an 85% decrease in total serum tryptophan. CONCLUSIONS: These data suggest that presynaptic serotonin availability may not be necessary for the acute maintenance of an antidepressant response to ECT.

Adult↗
PubMed1992

Synthesis and antihypertensive activity of 3-[(substituted-carbonyl)amino]-2H-1-benzopyrans.

The synthesis and antihypertensive activity of a series of novel 3-[(substituted-carbonyl)amino]-2H-1-benzopyran-4-ols, administered orally to spontaneously hypertensive rats, are described. Optimum activity in this series was observed for compounds with branched alkyl or branched alkylamino groups flanking the carbonyl or thiocarbonyl group (21, 31-33), which were approximately equipotent to cromakalim. Replacement of the 4-hydroxyl group by hydrogen, methoxy, or amino in this series only led to a slight reduction in potency. These observations are in marked contrast to the structure-activity relationships previously found for the 4-amidobenzopyran-3-ols. The antihypertensive activity of representative compounds 15 and 33 was attempted by preatreatment with glibenclamide, and thus these compounds may belong to the series of drugs which have been classified as potassium channel activators.

Animals↗
PubMed1992

Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.

The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.

Animals↗
PubMed1991

Synthesis and antihypertensive activity of pyran oxygen and amide nitrogen replacement analogues of the potassium channel activator cromakalim.

The synthesis and oral antihypertensive activity in conscious spontaneously hypertensive rats of two new series of compounds related to the prototype potassium channel activator cromakalim (1) are described. In the first series, replacement of the benzopyran oxygen atom by nitrogen or methylene led to the 1,2,3,4-tetrahydroquinoline 12 and 1,2,3,4-tetrahydronaphthalene 13, which were both less active than 1. However, in contrast to the equivalent activity found previously for 1 and its dehydrated analogue 28, the dihydronaphthalene 27 was found to be more active than 13. In the second series, replacement of the C(4) amide nitrogen atom in acyclic amides related to cromakalim by methylene gave ketone 16 that was less active than the corresponding amide 15. However, replacement of the 4-acetonyl substituent in 16 by N,N-dimethylacetamido as in compound 22 resulted in a marked enhancement in activity. The compounds described in this paper thus illustrate the importance of the benzopyran oxygen and C(4) substituent on antihypertensive activity in the cromakalim series of potassium channel activators.

Administration, Oral↗
PubMed1990

Synthesis and antihypertensive activity of 4-(substituted-carbonylamino)-2H-1-benzopyrans.

The synthesis and antihypertensive activity of a series of novel 4-(substituted-carbonylamino)-2H-1-benzopyran-3-ols, administered orally to conscious spontaneously hypertensive rats, are described. Optimum activity was observed for compounds with alkyl, amino, or aryl groups flanking the carbonyl group. Of the alkyl and amino series the most potent compounds contained the methyl and methylamino groups, respectively. Several analogues have been compared with cromakalim (1) for their effects on potassium ion efflux in the rabbit mesenteric artery using rubidium-86 as a marker. The ability of each compound to enhance rubidium-86 efflux is approximately parallelled by its blood pressure lowering activity, and thus these analogues, like compound (1), belong to the series of drugs which have been classified as potassium-channel activators.

Animals↗
PubMed1990

Variation in the aromatic ring of cromakalim: antihypertensive activity of pyranopyridines and 6-alkyl-2H-1-benzopyrans.

The synthesis and antihypertensive activity in the spontaneously hypertensive rat of two new series of analogues related to cromakalim (1) are described. In the first series, where the benzopyran nucleus has been replaced by a pyranopyridine nucleus, the position of the nitrogen atom has been found to be critical for activity, and the most potent compounds are the pyrano[3,2-c]pyridines. In the second series, where the powerful electron-withdrawing cyano group of compound 1 has been replaced by alkyl and phenyl groups, the order of antihypertensive potency is ethyl, isopropyl, tert-butyl greater than propyl, cyclopentyl greater than methyl greater than phenyl.

Animals↗
PubMed1987

Cardiac and microcirculatory effects of different doses of prostaglandin E1 in man.

A cumulative dose response to intravenous PGE1 was established in 12 healthy volunteers. Systolic time intervals, including pre-ejection period (PEP), the ventricular ejection time (VET) and the RR-interval, were continuously determined, and transcutaneous oxygen pressure (tcpO2) was recorded. RR-intervals fell in a dose dependent manner, reaching a significantly lower level at 128 ng.kg-1.min-1 of PGE1 (basal value 842 ms falling to 756 ms). PEP decreased from 89 ms to 74 ms and the ratio PEP/VET decreased from 35% to 30%, indicating increased myocardial contractility. The maximal increase in tcpO2 was 125% on the calf and 60% on the foot. The peak tcpO2 was observed at an infusion rate of 16 ng.kg-1.min-1 PGE1. A decline in tcpO2 was seen at infusion rates greater than 64 ng.kg-1.min-1 PGE1 indicating a decrease in skin perfusion. The results indicate that the effects of intravenous PGE1 on skin perfusion occur at a lower threshold than the increase in myocardial contractility. A maximal increase in skin perfusion can be achieved with doses of PGE1 devoid of systemic haemodynamic effects.

Adult↗
PubMed1987

Frequency- and orientation-dependent effects of mexiletine and quinidine on conduction in the intact dog heart.

Myocardial conduction depends on the magnitude of the fast inward sodium current as well as on cardiac fiber orientation, with more rapid propagation along myocardial fibers than across them. Although antiarrhythmic drugs depress the sodium current in a frequency-dependent fashion in vitro, their effects on conduction in the intact ventricle have been less well studied. We therefore evaluated the frequency- and orientation-dependent actions of mexiletine, quinidine, and their combination on epicardial conduction in 24 pentobarbital-anesthetized dogs. These interventions were chosen because the time constant of recovery from sodium-channel blockade by mexiletine in vitro is shorter than that from blockade by quinidine, and because we have previously shown that the combination of these drugs is often clinically effective when single-agent therapy fails. An electrode array that permitted measurement of conduction times in multiple orientations over short segments of epicardium without contamination by rapid Purkinje fiber propagation or by latency or virtual cathode effects at the stimulus site was developed for these studies. In all animals, the atrioventricular node was destroyed by injection of formalin to permit measurements over a wide range of cycle lengths (250 to 1500 msec). In the absence of drugs, conduction in any direction was frequency independent. In the presence of mexiletine, however, frequency-dependent increases in conduction times were found at cycle lengths of 600 msec or less; these changes were significantly greater in orientations for which baseline conduction was rapid. Quinidine, on the other hand, increased conduction times at all tested cycle lengths without significant orientation-dependent effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Activity of the oxidation products of oleum terebinthinae "Landes" on guinea pig airway smooth muscle in vivo and in vitro.

The oxidation products of Oleum Terebinthinae "Landes" (Ozothin; in the following briefly called Ox. O. T. L.) have been described in many studies as being of benefit in the treatment of disturbed tracheobronchial function in obstructive airways diseases. Previous literature has dealt mainly with the influence of Ox. O. T. L. on the visco-elastic properties of mucus. However, the purpose of the present work was to study the bronchospasmolytic component. Using a standard methodology for the measurement of bronchospasmolytic effects, it could be demonstrated that Ox.O.T.L., given orally or as an aerosol, protected conscious guinea pigs against histamine-induced bronchoconstriction. The potency was lower than that of isoprenaline but was significant and reproducible. These results in vivo are paralleled by effects observed on guinea pig lung strips and tracheal spiral preparations. Ox.O.T.L. relaxed, in a dose-dependent fashion, guinea pig lung strip preparations contracted with histamine. Potency and efficacy was, however, less than that of isoprenaline. Similarly, in guinea pig tracheal spiral preparations, Ox.O.T.L. was less potent than isoprenaline in counteracting carbachol-elevated tone. However, efficacy equalled that of isoprenaline. Ox.O.T.L. was approximately 3 times more potent in the isolated tracheal spiral preparation than in lung strips. The activity of non-oxidised turpentine oil and terpin hydrate against histamine-induced bronchoconstriction in conscious animals and in the isolated organ preparations was substantially lower than that of the oxidation products of O.T.L.

Administration, Oral↗
PubMed1986

Sodium nuclear magnetic resonance imaging of myocardial tissue of dogs after coronary artery occlusion and reperfusion.

Nuclear magnetic resonance (NMR) imaging techniques have been applied to the observation of tissue sodium-23 in normal and ischemic canine myocardium. To produce a region of ischemia and infarction in the myocardium, in six dogs a coronary artery was subjected to 1 hour of surgical occlusion followed by 1 hour of reperfusion. The dogs were then killed and sodium-23 NMR images of the excised hearts were obtained using a high field NMR imaging system. These images were compared with tissue sodium contents measured by flame photometry. The regions of ischemic damage were clearly visible as areas of increased sodium NMR signal on the three-dimensional images. A good correspondence was found between the relative intensity of the sodium signals and the sodium contents of normal myocardium and myocardium subjected to coronary artery occlusion and reperfusion. The data suggest the feasibility of NMR sodium imaging to detect the location and extent of myocardial damage in patients with coronary artery disease.

Animals↗
PubMed1986

Synthesis and antihypertensive activity of 4-(cyclic amido)-2H-1-benzopyrans.

The synthesis and antihypertensive activity of a series of novel 4-(cyclic amido)-2H-1-benzopyran-3-ols, administered orally to conscious spontaneously hypertensive rats, are described. The effects of lactam ring size, the presence of heteroatoms in the lactam ring, substitution at C(2) and C(3), relative stereochemistry at C(3) and C(4), and aromatic substitution pattern on the blood pressure lowering activity of this series have been determined. The key compound 2 from this work [BRL 34915; (+/-)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxopyrrolidin-1- yl)-2H-1-benzopyran-3-ol] has been resolved, and antihypertensive activity was found to reside primarily in the (-) enantiomer. The key step in the preparation of this class of compounds is the action of a cyclo amidic anion on an appropriate epoxide. Another approach, involving a cyclization step to the lactam was found to be more convenient in certain cases, particularly in forming the cis analogue of compound 2. Compound 2 has been shown to possess a novel mechanism of action, and it has been selected for progression to the clinic.

Animals↗
PubMed1978

An example of how patient selection can influence survival in glioblastoma multiforme.

Drawing on experience in evaluating postsurgical treatment of glioblastoma multiforme, it is concluded that results of clinical trials programs can be greatly affected by the status of patients who are selected for study. Investigations report results only on patients considered "evaluable," a portion of the total which may be less than 20%. Improvement in patient survival should not be conceived to be due to aggressive treatment unless patient selection has been accounted for.

Brain Neoplasms↗