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Biomedical subjects

Charles P O'Brien

Publications and source records attributed to Charles P O'Brien.

52 records · Page 3Linked to original sources
PubMed2003

Alcohol potentiates hepatitis C virus replicon expression.

Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (HCV) effect of interferon alfa (IFN-alpha) in patients with HCV infection. It is unknown, however, whether alcohol enhances HCV replication and promotes HCV disease progression. The availability of the HCV replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and HCV replicon expression. We determined whether alcohol enhances HCV RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-alpha. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor kappaB (NF-kappaB) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression. In conclusion, alcohol, probably through the activation of NF-kappaB and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-alpha. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-alpha-based therapy against HCV infection.

Antidotes↗
PubMed2003

A genetic association study of the mu opioid receptor and severe opioid dependence.

OBJECTIVES: Twin, family and adoption studies have suggested that vulnerability to opioid dependence may be a partially inherited trait (Cadoret et al., 1986; Merikangas et al., 1998; Tsuang et al., 1998, 2001). Studies using animal models also support a role for genetic factors in opioid dependence, and point to a locus of major effect on mouse chromosome 10 (Berrettini et al., 1994; Alexander et al., 1996), which harbors the mu opioid receptor gene (Mor1) (Kozak et al., 1994). The gene encoding the human mu opioid receptor (OPRM1) is thus an obvious candidate gene for contributing to opioid dependence. A recent report (Hoehe et al., 2000) found a significant association between a specific combination of OPRM1 single nucleotide polymorphisms (SNPs) and substance dependence. METHODS: In the current study, we genotyped 213 subjects with severe opioid dependence (89 African-Americans, 124 European-Americans) and 196 carefully screened "supercontrol" subjects (96 African-Americans, 100 European-Americans) at five SNPs residing in the OPRM1 gene. The polymorphisms include three in the promoter region (T-1793A, -1699T insertion and A-1320G) and two in exon 1 (C+17T [Ala6Val] and A+118G [Asp40Asn]). RESULTS: Statistical analysis of the allele frequency differences between opioid-dependent and control subjects for each of the polymorphisms studied yielded P values in the range of 0.444-1.000. Haplotype analysis failed to identify any specific combination of SNPs associated with the phenotype. CONCLUSIONS: Despite reasonable statistical power we found no evidence of association between the five mu opioid receptor polymorphisms studied and severe opioid dependence in our sample. There were, however, significant allele frequency differences between African-Americans and European-Americans for all five polymorphisms, irrespective of drug-dependent status. Linkage disequilibrium analysis of the African-American genotypes indicated linkage disequilibrium (P<0.0001) across the five-polymorphism, 1911 base pair region. In addition, only four haplotypes of these five polymorphisms are predicted to exist in African-Americans.

Base Sequence↗
PubMed2003

Research advances in the understanding and treatment of addiction.

The likelihood of developing an addictive disorder is a function of multiple simultaneous, pharmacologic, genetic, and environmental variables, such as the pharmacology of the drug, the route of administration, the personality of the individual, and the availability of the drug. There is increasing evidence that long-lasting changes in the brain result from the progression of casual user to addict. Moreover, the course of the progression of addiction is similar to that of other chronic diseases. In this paper, strategies for effective treatment of addiction, including long-term relapse management and new pharmacological therapies such as naltrexone and acamprosate, are discussed.

Acamprosate↗
PubMed2002

A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients.

The NMDA antagonist dextromethorphan hydrobromide (DM) may be useful in the treatment of opioid dependence, particularly as a means of reducing tolerance to methadone during replacement therapy. As a prelude to clinical efficacy studies, a randomized, double-blind, placebo-controlled study examined the safety of DM in combination with methadone in inpatient, opiate-dependent volunteers. Male participants received daily methadone (50-70 mg/day) and either DM (n=10) or placebo (n=5) during the 12-day active medication phase of the study. DM participants received doses of 120, 240, and 480 mg/day in increasing order (4 days each). DM at high doses caused mild elevations of heart rate, blood pressure, temperature, and plasma bromide. However, none of these effects was clinically significant. DM caused no significant changes in respiration, pupil diameter, or subjective drug effects measured by standard scales. Participants in the DM group reported many more adverse events than did subjects on placebo (173 vs. 21), but these effects were not clinically serious. The most commonly reported side effects were sleepiness and drowsiness. Several participants reported intoxicating effects at the highest dose. Overall, DM was well-tolerated by the methadone-maintained opiate-dependent subjects studied here. These results support the further exploration of DM as an adjunct medication during methadone replacement therapy.

Adult↗
PubMed2002

Comparing attentional bias to smoking cues in current smokers, former smokers, and non-smokers using a dot-probe task.

Much evidence documents that individuals with emotional and drug-use disorders demonstrate biased attention toward stimuli associated with their disorder. This bias appears to diminish following successful treatment. Two studies examined whether current cigarette smokers show biased attention toward smoking-related images compared with non-smokers (Studies 1 and 2) and whether this bias is less pronounced in former smokers (Study 2). Attentional bias toward cigarette-related photographs was examined using the dot-probe task. Pairs of images (one smoking-related) appeared side by side for 500 ms on a computer screen prior to the presentation of a probe (an asterisk) replacing one of the photographs. Subjects struck a key as quickly as possible to indicate the probe location. Attentional bias was defined as faster reaction times when the probe replaced the smoking-related image. In both studies, current smokers displayed significantly greater attentional bias toward cigarette stimuli than did non-smokers. Former smokers in Study 2 displayed an intermediate level of bias, but did not differ significantly in bias score from either of the other groups. These results support further use of the dot-probe task as a measure of attentional bias in non-abstinent smokers and in individuals undergoing smoking cessation treatment.

Adult↗
PubMed2002

Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients.

BACKGROUND: Structural deficiencies within limbic and prefrontal regions may contribute to the characteristic drug-seeking and drug-taking behaviors that prevail in persons dependent on cocaine. To date, a focal structural analysis of the brains of cocaine patients has not been undertaken. METHODS: We used voxel based morphometry in conjunction with statistical parametric mapping on the structural magnetic resonance images of cocaine-dependent (n = 13) and cocaine-naive individuals (n = 16) to assess differences between the two groups in gray and white matter concentration. RESULTS: We report a decrease in gray matter concentration in the ventromedial orbitofrontal, anterior cingulate, anteroventral insular, and superior temporal cortices of cocaine patients in comparison to controls (p <.01 corrected for multiple comparisons). The average percentage decrease in gray matter concentration within a region ranged from 5% to 11%. White matter concentration did not differ between groups. CONCLUSIONS: We conclude that the brains of cocaine patients are structurally dissimilar from those of nondrug-using controls. The differences were detected in regions involved in decision-making, behavioral inhibition and assignation of emotional valence to environmental stimuli and, hence, may contribute to some of the behavioral deficits characteristic of chronic cocaine users.

Adult↗
PubMed2002

Detecting smoking following smoking cessation treatment.

Our study compared the results of self-report (SR) plus breath carbon monoxide (CO) monitoring to SR plus urine cotinine (COT) analysis of recent tobacco use for a recently completed smoking cessation study that compared the efficacy of different intensities of psychosocial treatments coupled with 8 weeks of patch treatment. Treatment outcomes were assessed 9, 26, and 52 weeks from treatment initiation in 200+ patients using both measurement types. COT was able to detect self-reported smoking in over 97% of the cases at all time points, while CO detected self-reported smoking 62, 84, and 89% of the time for the three follow-up assessments. Under 2% of those reporting nonsmoking were found to be smoking via CO, whereas COT found smoking to have occurred for 23, 15, and 7% of the 'nonsmoking' SRs at the three time points. Abstinence rates using SR plus CO were 49, 29, and 26%, contrasted with abstinence rates of 38, 26, and 25% for SR plus COT. These findings suggest that use of urine analysis for COT may lead to more accurate but lowered measured abstinence rates.

Adult↗
PubMed2002

A comparison of the effects of 6-beta naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited-access procedure in rats.

We recently reported that 6-beta naltrexol, the major metabolite of naltrexone in humans, reduced ethanol consumption in rats. Two new experiments were designed to compare 6-beta naltrexol and naltrexone across three dose levels on an ethanol or sucrose baseline using a limited-access procedure in Wistar rats. The results of Experiment 1 showed that both 6-beta naltrexol and naltrexone reduced ethanol consumption across a range of doses. An in vivo assay showed that naltrexone was approximately 25 times more potent than 6-beta naltrexol at comparable ED50 doses. In addition, there was no indication of systematic development of tolerance to the effect of either drug across the 4 days of drug administration. In Experiment 2, both 6-beta naltrexol and naltrexone reduced the consumption of a sucrose solution using a limited-access procedure. The implications of these data for the development of pharmacotherapeutic agents capable of reducing drinking in recovering alcoholics are discussed.

Alcohol Drinking↗
PubMed2002

Effect of naltrexone on oral consumption of concurrently available ethanol and cocaine in the rat.

Comorbid abuse of and dependency on multiple drugs is a common occurrence clinically. We have developed an animal model that provides rats with the opportunity to choose, through oral consumption, between concurrently available ethanol and cocaine with water also available. This provides the ability to screen for the effectiveness of potential pharmacotherapeutic agents on the baseline consumption of both drugs. We used this animal model to evaluate the effects of naltrexone, at doses of 0, 1.0, 3.0, and 10.0 mg/kg, on concurrent oral consumption of ethanol and cocaine solutions. Naltrexone at all doses significantly reduced both consumption of and preference for ethanol. Consumption of both cocaine and water was unaffected by naltrexone, supporting the suggestion that the effects of naltrexone were selective for ethanol. These findings support the suggestion that ethanol and cocaine act on different central reward pathways. The implications of these findings for the clinical use of naltrexone in populations with comorbid ethanol and cocaine abuse are discussed.

Administration, Oral↗
PubMed2002

Alcohol potentiates HIV-1 infection of human blood mononuclear phagocytes.

BACKGROUND: Acute and chronic alcohol abuse impairs various functions of the immune system and thus has been implicated as a cofactor in HIV infection. The mechanisms by which alcohol affects the function of human immune cells that are the targets for HIV are unknown. METHODS: Human blood monocyte-derived macrophages (MDM) were incubated with or without alcohol (10-40 mM) for 24 hr and then infected with HIV for 24 hr. Culture supernatants were harvested for HIV reverse transcription assay. HIV entry receptor (CCR5, CD4, and CXCR4) expression was determined by reverse transcription-polymerase chain reaction and flow cytometry assays. Beta-chemokines were analyzed using enzyme-linked immunosorbent assay. Different HIV strains (Bal, SF-162, 89.6, and UG024) were used for infection experiments. In addition, ADA (macrophage-tropic strain) and murine leukemia virus envelope-pseudotyped HIV infection was carried out. RESULTS: Although alcohol had little effect on HIV T-lymphocyte-tropic strain infection, it significantly enhanced HIV R5 strain infection in MDM. The enhancing effect of alcohol on the HIV R5 strain was further evidenced by the observation that the R5 (ADA) strain envelope-pseudotyped HIV infection is markedly increased by alcohol, whereas murine leukemia virus envelope-pseudotyped HIV infection was not affected. Alcohol significantly up-regulated CCR5 receptor expression and inhibited the endogenous production of beta-chemokines by MDM. CONCLUSION: Alcohol, through the down-regulation of beta-chemokine production and the up-regulation of CCR5 receptor expression, enhances HIV R5 strain infection of MDM and may have an important role as a cofactor in the progression of HIV disease.

Cells, Cultured↗
PubMed2002

Cynthia'a dilemma.

Explore the source record for details and available documents.

Clinical Trials as Topic↗
PubMed2002

Concurrent cocaine withdrawal alters alcohol withdrawal symptoms.

This study compares alcohol withdrawal severity during outpatient detoxification in alcohol dependent subjects (ALC) and in subjects dependent on both alcohol and cocaine (ALC/COC). Subjects included 123 ALC and 66 ALC/COC subjects. Baseline demographic and drug use variables, alcohol withdrawal symptoms, and the total amount of oxazepam taken during alcohol detoxification were compared between the two groups. Compared to ALC subjects, ALC/COC subjects were younger, more likely to be African-American, and had less severe histories of alcohol dependence. However, alcohol withdrawal symptom severity did not differ significantly between the two groups. Nevertheless, controlling for differences in alcohol use history, ALC/COC subjects still received less oxazepam than did ALC subjects to treat alcohol withdrawal symptoms. Despite similar intensity of alcohol withdrawal symptoms, ALC/COC subjects received less oxazepam to treat alcohol withdrawal symptoms compared to ALC subjects. Both subject and clinician factors may explain the difference in oxazepam use.

Adolescent↗
PubMedDate not supplied

Cocaine withdrawal severity and urine toxicology results from treatment entry predict outcome in medication trials for cocaine dependence.

Both cocaine withdrawal symptoms, measured by an instrument called the Cocaine Selective Severity Assessment (CSSA), and urine toxicology results obtained at the start of treatment have been shown to predict treatment outcome in outpatient cocaine dependence treatment. This study further evaluates the predictive validity of the CSSA and urine toxicology results, alone and in combination. Subjects included 76 cocaine-dependent individuals who participated in 7-week, outpatient, pilot medication trials for cocaine dependence. Predictor variables included CSSA scores and results from a urine toxicology screen obtained on the first day of medication treatment. Successful outcome was defined as 3 continuous weeks of self-reported abstinence from cocaine confirmed by urine toxicology screens. Predictive validity was assessed by logistic regression analysis. Both the urine toxicology screen and the CSSA scores were significant predictors of 3 weeks of continuous abstinence from cocaine, and the inclusion of both variables significantly improved the predictive validity of either variable alone. Urine toxicology results and CSSA scores obtained at treatment entry are useful predictors of outcome in outpatient cocaine dependence treatment.

Adolescent↗
PubMedDate not supplied

Cocaine dependence severity predicts outcome in outpatient detoxification from cocaine and alcohol.

This study compared the effects of alcohol and cocaine dependence severity on the outcome of outpatient detoxification from alcohol and cocaine. Subjects included 84 subjects with both alcohol and cocaine dependence admitted for outpatient detoxification. Fifty-three of the 84 subjects (63%) completed detoxification. Baseline cocaine use, cocaine craving, and cocaine withdrawal symptoms predicted detoxification outcome, whereas alcohol use, alcohol craving, and alcohol withdrawal symptoms did not. Among cocaine- and alcohol-dependent subjects, cocaine dependence severity appears to be a more important predictor of detoxification success than alcohol dependence severity.

Adult↗