PubMed Health⌕ Search

Biomedical subjects

S O'Malley

Publications and source records attributed to S O'Malley.

At least 19 recordsLinked to original sources
PubMed2001

Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers.

Nicotine and other constituents of tobacco smoke elevate dopamine (DA) and serotonin (5-HT) levels in brain and may cause homeostatic adaptations in DA and 5-HT transporters. Since sex steroids alter DA and 5-HT transporter expression, the effects of smoking on DA and 5-HT transporter availability may differ between sexes. In the present study, DA and 5-HT transporter availabilities were quantitated using single photon emission computed tomography (SPECT) imaging approximately 22 h after bolus administration of [123I]beta-CIT, an analog of cocaine which labels DA and 5-HT transporters. Forty-two subjects including 21 pairs of age-, race-, and gender-matched healthy smokers and nonsmokers (12 female and 9 male pairs) were imaged. Regional uptake was assessed by the outcome measures, V3", which is the ratio of specific (i.e., ROI-cerebellar activity) to nondisplaceable (cerebellar) activity, and V3, the ratio of specific to free plasma parent. Overall, striatal and diencephalic [123I]beta-CIT uptake was not altered by smoking, whereas brainstem [123I]beta-CIT uptake was modestly higher (10%) in smokers vs. nonsmokers. When subgrouped by sex, regardless of smoking status, [123I]beta-CIT uptake was higher in the striatum (10%), diencephalon (15%), and brainstem (15%) in females vs. males. The sex*smoking interaction was not significant in the striatum, diencephalon, or brainstem, despite the observation of 20% higher brainstem [123I]beta-CIT uptake in male smokers vs. nonsmokers and less than a 5% difference between female smokers and nonsmokers. The results demonstrate higher DA and 5-HT transporter availability in females vs. males and no overall effect of smoking with the exception of a modest elevation in brainstem 5-HT transporters in male smokers. Although these findings are preliminary and need validation with a more selective 5-HT transporter radiotracer, the results suggest that brainstem 5-HT transporters may be regulated by smoking in a sex-specific manner.

Adult↗
PubMed2001

Application of cocaine to the nasal mucosa: a novel method.

Topical vasoconstriction using four to 10 per cent cocaine is widely used for nasal surgery. A number of techniques are being used with equally satisfactory results. Here we describe a novel method of topical application of cocaine for nasal surgery. The method is simple, cheap and effective.

Administration, Topical↗
PubMed2000

Immunoassays with rolling circle DNA amplification: a versatile platform for ultrasensitive antigen detection.

We describe an adaptation of the rolling circle amplification (RCA) reporter system for the detection of protein Ags, termed "immunoRCA. " In immunoRCA, an oligonucleotide primer is covalently attached to an Ab; thus, in the presence of circular DNA, DNA polymerase, and nucleotides, amplification results in a long DNA molecule containing hundreds of copies of the circular DNA sequence that remain attached to the Ab and that can be detected in a variety of ways. Using immunoRCA, analytes were detected at sensitivities exceeding those of conventional enzyme immunoassays in ELISA and microparticle formats. The signal amplification afforded by immunoRCA also enabled immunoassays to be carried out in microspot and microarray formats with exquisite sensitivity. When Ags are present at concentrations down to fM levels, specifically bound Abs can be scored by counting discrete fluorescent signals arising from individual Ag-Ab complexes. Multiplex immunoRCA also was demonstrated by accurately quantifying Ags mixed in different ratios in a two-color, single-molecule-counting assay on a glass slide. ImmunoRCA thus combines high sensitivity and a very wide dynamic range with an unprecedented capability for single molecule detection. This Ag-detection method is of general applicability and is extendable to multiplexed immunoassays that employ a battery of different Abs, each labeled with a unique oligonucleotide primer, that can be discriminated by a color-coded visualization system. ImmunoRCA-profiling based on the simultaneous quantitation of multiple Ags should expand the power of immunoassays by exploiting the increased information content of ratio-based expression analysis.

Animals↗
PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.

Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety.

We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.

Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.

Adrenergic alpha-Antagonists↗
PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 4. Structure-activity relationship in the dihydropyrimidine series.

We have previously disclosed dihydropyridines such as 1a,b as selective alpha(1a) antagonists as a potential treatment for benign prostatic hyperplasia (BPH). The propensity of dihydropyridines toward an oxidation led us to find suitable replacements of the core unit. The accompanying papers describe the structure-activity relationship (SAR) of dihydropyrimidinones 2a,b as selective alpha(1a) antagonists. We report herein the SAR of dihydropyrimidines such as 4 and highlight the similarities and differences between the dihydropyrimidine and dihydropyrimidinone series of compounds.

Administration, Oral↗
PubMed1999

Stress-induced craving and stress response in cocaine dependent individuals.

Two laboratory studies were conducted to examine the effects of acute psychological stress on craving and stress reactivity in cocaine abusers. In the first preliminary study, we examined the effects of a speech stressor task and a personalized stress imagery task on self-reported craving and emotional state in ten cocaine abusers. Both stressors led to significant decreases in neutral and joy states, and significant increases in fear ratings as compared to baseline ratings. In addition, the stress imagery condition led to significant increases in cocaine craving and sadness and anger ratings, as compared to baseline. Thus, the personalized stress imagery task appeared to be more effective than the speech stress task in inducing craving in the laboratory. The second study examined the effects of stress imagery as compared to neutral imagery on cocaine craving, subjective anxiety and physiological responses in a second group of ten cocaine abusers. The stress imagery task once again produced significant increases in cocaine craving along with increases in heart rate, salivary cortisol and subjective anxiety ratings. These data are the first to document that acute psychological stress consistently increases craving for cocaine in cocaine abusers. The studies also provide a promising method for examining the association between stress and drug craving in the laboratory.

Adult↗
PubMed1999

Rapid exchange of A:T base pairs is essential for recognition of DNA homology by human Rad51 recombination protein.

Human Rad51 belongs to a ubiquitous family of proteins that enable a single strand to recognize homology in duplex DNA, and thereby to initiate genetic exchanges and DNA repair, but the mechanism of recognition remains unknown. Kinetic analysis by fluorescence resonance energy transfer combined with the study of base substitutions and base mismatches reveals that recognition of homology, helix destabilization, exchange of base pairs, and initiation of strand exchange are integral parts of a rapid, concerted mechanism in which A:T base pairs play a critical role. Exchange of base pairs is essential for recognition of homology, and physical evidence indicates that such an exchange occurs early enough to mediate recognition.

Adenine↗
PubMed1999

Giant cell tumour of the hyoid--first reported case.

Giant cell tumours of bone are most commonly found in the epiphyses of weight-bearing long bones. They are rarely found in the head and neck and only 17 cases involving the laryngeal framework have been reported. To date, there have been no reports of a giant cell tumour arising from the hyoid bone. We present such a case which presented as a lump overlying the greater cornu of the hyoid, review the literature and discuss the management of this locally aggressive tumour.

Adult↗
PubMed1999

Variable dose naltrexone-induced hypothalamic-pituitary-adrenal stimulation in abstinent alcoholics: a preliminary study.

Opiate antagonists have been found to stimulate the hypothalamic-pituitary-adrenal axis. However, despite established usefulness in the management of alcoholism, systematic, oral dose-titrated natrexone-induced hypothalamic-pituitary-adrenal stimulation has never been studied in alcoholics. Six patients (5 males, 1 female) with DSM-IV alcohol dependence, who were at least 4 weeks abstinent from any alcohol [mean 55 days (+/-SE 7.5)], were given four challenges of oral naltrexone (0, 25, 50, and 100 mg) in a randomized order at least 3 days apart, after an overnight fast. Naltrexone was administered at 9 AM; serum ACTH, cortisol, and prolactin were measured at time 0 and at 9 time points over the next 4 hr. Subjects also filled out a side effect questionnaire and an alcohol urge questionnaire. Physiological measurements of blood pressure and pulse rate were taken at the same time points. Repeated-measures ANOVA of the changes in serum ACTHs over time revealed a significant effect of drug (placebo vs. any dose of naltrexone) (p < 0.05). Post-hoc analysis revealed a significant difference between placebo and the 25 mg dose (p < 0.01), the 50 mg dose (p < 0.01), but no significance between the placebo and the 100 mg dose (p = 0.1). A repeated-measures ANOVA of the changes in serum cortisols over time revealed a significant effect of drug (p < 0.01). Post-hoc analysis revealed a significant difference between placebo and the 25 mg dose (p < 0.01), between placebo and the 50 mg dose (p < 0.05), and placebo and the 100 mg dose (p < 0.01). There was a significant between dose difference in pulse rate changes over baseline (p < 0.01), and post-hoc analysis revealed a significant diminution in pulse rate at the 100 mg dose relative to placebo (p < 0.001), and to the other doses. There were no significant differences in reported side effects, alcohol urge questionnaire scores, or in other physiological measurements between doses. These data suggest a significant rise in ACTH and cortisol in response to naltrexone in alcoholics compared with placebo, with no differences between 25 mg, 50 mg, and 100 mg doses, and a significant diminution in pulse rate responses at the 100 mg dose.

Adrenocorticotropic Hormone↗
PubMed1998

Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.

Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1998

Stress response dampening: effects of gender and family history of alcoholism and anxiety disorders.

One hundred and fifteen non-alcoholic social drinkers, ages 21-30 years, were selected on the basis of parental history of alcoholism and/or anxiety disorders to participate in a laboratory study of stress response dampening (SRD) effects of alcohol. The following four risk groups were identified based on the diagnoses of both parents: 1) alcoholism (ALC+), (2) alcoholism and anxiety disorder (ALCANX+), (3) anxiety (ANX+), and (4) no psychiatric diagnoses (FH-). Subjects were randomly assigned to receive a placebo or alcohol (0.85 g/kg) beverage, following which cardiovascular measures and self-reports of anxiety were monitored prior to, during and after a speech stressor. Women with a family history of alcoholism and women with a family history of anxiety disorders showed strong SRD effects of alcohol on heart rate and pulse transit time. Men with a family history of anxiety disorders showed evidence of increased subjective response to stress during the alcohol beverage condition. Finally, SRD effects of alcohol were not found for male subjects, and this was attributed to their heavier drinking histories and lower breath alcohol levels as compared to women. Implications of the SRD effects in women are discussed in the context of the comorbid association between alcoholism and anxiety disorders.

Adult↗
PubMed1998

Co-morbidity and familial aggregation of alcoholism and anxiety disorders.

BACKGROUND: This study examined the patterns of familial aggregation and co-morbidity of alcoholism and anxiety disorders in the relatives of 165 probands selected for alcoholism and/or anxiety disorders compared to those of 61 unaffected controls. METHODS: Probands were either selected from treatment settings or at random from the community. DSM-III-R diagnoses were obtained for all probands and their 1053 first-degree relatives, based on direct interview or family history information. RESULTS: The findings indicate that: (1) alcoholism was associated with anxiety disorders in the relatives, particularly among females; (2) both alcoholism and anxiety disorders were highly familial; (3) the familial aggregation of alcoholism was attributable to alcohol dependence rather than to alcohol abuse, particularly among male relatives; and (4) the the pattern of co-aggregation of alcohol dependence and anxiety disorders in families differed according to the subtype of anxiety disorder; there was evidence of a partly shared diathesis underlying panic and alcoholism, whereas social phobia and alcoholism tended to aggregate independently. CONCLUSIONS: The finding that the onset of social phobia tended to precede that of alcoholism, when taken together with the independence of familial aggregation of social phobia and alcoholism support a self-medication hypothesis as the explanation for the co-occurrence of social phobia and alcoholism. In contrast, the lack of a systematic pattern in the order of onset of panic and alcoholism among subjects with both disorders as well as evidence for shared underlying familial risk factors suggests that co-morbidity between panic disorder and alcoholism is not a consequence of self-medication of panic symptoms. The results of this study emphasize the importance of examining co-morbid disorders and subtypes thereof in identifying sources of heterogeneity in the pathogenesis of alcoholism.

Alcoholism↗
PubMed1998

The population-based approach to chronic care.

Looking at the needs of a population rather than the episodes that land individuals in the hospital is one way to improve care. Find out the 10 steps to establishing population-based care programs, and learn some healthcare organizations' strategies for preventing acute episodes.

Chronic Disease↗