PubMed Health⌕ Search

Biomedical subjects

Charles P O'Brien

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

At least 37 records · Page 2Linked to original sources
PubMed2005

Critical assessment of how to study addiction and its treatment: human and non-human animal models.

Laboratory models, both animal and human, have made enormous contributions to our understanding of addiction. For addictive disorders, animal models have the great advantage of possessing both face validity and a significant degree of predictive validity, already demonstrated. Another important advantage to this field is the ability of reciprocal interplay between preclinical and clinical experiments. These models have made important contributions to the development of medications to treat addictive disorders and will likely result in even more advances in the future. Human laboratory models have gone beyond data obtained from patient histories and enabled investigators to make direct observations of human drug self-administration and test the effects of putative medications on this behavior. This review examines in detail some animal and human models that have led not only to important theories of addiction mechanisms but also to medications shown to be effective in the clinic.

Animals↗
PubMed2005

A double-blind, placebo-controlled trial of modafinil for cocaine dependence.

Despite years of active research, there are still no approved medications for the treatment of cocaine dependence. Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions, and the current study assessed whether modafinil would improve clinical outcome in cocaine-dependent patients receiving standardized psychosocial treatment. This was a randomized, double-blind, placebo-controlled trial conducted at a university outpatient center (from 2002 to 2003) on a consecutive sample of 62 (predominantly African American) cocaine-dependent patients (aged 25-63) free of significant medical and psychiatric conditions. After screening, eligible patients were randomized to a single morning dose of modafinil (400 mg), or matching placebo tablets, for 8 weeks while receiving manual-guided, twice-weekly cognitive behavioral therapy. The primary efficacy measure was cocaine abstinence based on urine benzoylecgonine levels. Secondary measures were craving, cocaine withdrawal, retention, and adverse events. Modafinil-treated patients provided significantly more BE-negative urine samples (p=0.03) over the 8-week trial when compared to placebos, and were more likely to achieve a protracted period (> or =3 weeks) of cocaine abstinence (p=0.05). There were no serious adverse events, and none of the patients failed to complete the study as a result of adverse events. This study provides preliminary evidence, which should be confirmed by a larger study, that modafinil improves clinical outcome when combined with psychosocial treatment for cocaine dependence.

Adult↗
PubMed2005

Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population.

OBJECTIVE: While twin and adoption studies have demonstrated that up to 70% of the risk for becoming addicted to cocaine is due to genetic factors, identifying specific genes involved in the development or progression of cocaine dependence has been difficult. The purpose of this study is to determine whether single-nucleotide polymorphisms in the Homer1 and Homer2 genes associate with the cocaine-dependent phenotype in an African American population. METHODS: This study utilized a case-control design in which the genotype and allele frequencies for four single-nucleotide polymorphisms in the Homer1 gene and three single-nucleotide polymorphisms in the Homer2 gene were compared between African American individuals with a diagnosis of cocaine dependence (n=170) and African American individuals with no history of substance abuse (n=90). RESULTS: The data indicate that one single-nucleotide polymorphism, rs6871510, located in intron 1 of the Homer1 gene significantly (P=0.029) associates with cocaine dependence at the genotype level, and trends toward a significant association at the allele frequency level (chi=2.62, df=1, P=0.106, OR=1.71). None of the single-nucleotide polymorphisms analyzed in the Homer2 gene associates with cocaine dependence. CONCLUSIONS: The results of this study suggest that a polymorphism in the Homer1 gene, rs6871510, is a potential risk factor for the development of cocaine dependence in an African American population, whereas polymorphisms in the Homer2 gene are not.

Black People↗
PubMed2005

A functional prodynorphin promoter polymorphism and opioid dependence.

OBJECTIVES: The prodynorphin gene (PDYN) promoter has a repeat polymorphism that is functionally important in association with substance abuse. We examined this polymorphism for association in our sample of 168 opioid-dependent patients and 122 ethnically and geographically matched controls. METHODS: Patients were selected from university-affiliated residential and non-residential addiction treatment programs in the Philadelphia area. A sample of blood was drawn from consenting individuals and genomic DNA was isolated. Polymerase chain reaction amplification of the PDYN promoter was performed and various genotypes were determined on the basis of differing sizes of the polymerase chain reaction products. The genotype and allele data were analyzed by Fisher's exact test. RESULT: A significant difference in genotype (P<0.0006) and allele (P<10) frequencies was found between the African American and European American populations. We did not detect any significant difference in genotype or allele frequencies between the patients and controls within the European American ethnic group. However, we detected a weak association (P=0.013) when we compared allele frequencies of patients and controls in the African American population. CONCLUSIONS: These data suggest that the PDYN repeat polymorphism should be studied in additional opioid-dependent populations.

Enkephalins↗
PubMed2005

Alcohol suppresses IL-2-induced CC chemokine production by natural killer cells.

BACKGROUND: Natural killer (NK) cells are a critical component of the host innate immune system. We investigated whether alcohol impairs NK cell function, particularly production of CC chemokines induced by interleukin (IL)-2, the natural ligands for CCR5 receptor. METHODS: Primary NK cells and NK cell line (YTS) were cultured with or without alcohol (10 to 80 mM) for three hours. The culture supernatants were then harvested and used to treat human peripheral blood monocyte-derived macrophages and a HeLa cell line, which expresses CD4, CCR5, and CXCR4 receptors (MAGI cells). CC chemokine expression by YTS and primary NK cells treated with or without alcohol was analyzed with the real-time RT-PCR and ELISA. [Ca(2)(+)]i and Western blot assays were used to determine calcium-mediated intracellular signaling pathway and NF-kappaB p65 expression. HIV strains (Bal and UG024) were used to infect macrophages and MAGI cells. In addition, ADA (macrophage-tropic strain) and murine leukemia virus (MLV) envelope-pseudotyped HIV infection was carried out in macrophages. HIV infectivity was determined by HIV reverse transcriptase (RT) and beta-galactosidase activity assays. RESULTS: Alcohol inhibited IL-2-induced CC chemokine (CCL3 and CCL4) expression by NK cells. Functional tests demonstrated that this reduced expression of CC chemokines was associated with diminished anti-HIV ability of NK cells. Alcohol also reduced the ability of NK cells to response to CCL3-mediated chemotaxis. Alcohol inhibited IL-2-induced NF-kappaB p65 protein expression and calcium mobilization by NK cells. CONCLUSIONS: Alcohol, through the inhibition of IL-2-induced NF-kappaB p65 protein expression and intracellular calcium mobilization, suppressed NK cell production of CC chemokines. This suppression of CC chemokine production was associated with diminished anti-HIV activity of NK cells. Thus, by inhibiting NK cell-mediated innate immunity against HIV, alcohol consumption may have a cofactor role in the immunopathogenesis of HIV disease.

Adult↗
PubMed2005

Anticraving medications for relapse prevention: a possible new class of psychoactive medications.

Psychiatrists have gradually developed a list of medications that are effective in the treatment of addictive disorders. Although alcoholism has received the most attention, nicotine, heroin, and cocaine have all been shown to be influenced by heredity. Of course, the immediate goal is the reduction of drug craving and the prevention of relapse to compulsive drug taking. A medication that can aid in the maintenance of the opiate-free state is naltrexone, a specific opiate antagonist. Naltrexone is also a good example of an anticraving medication used in the treatment of alcoholism. Clinicians currently have two types of medication to aid in the treatment of tobacco use disorder, arguably the most important addiction. Bupropion and nicotine replacement can be given in a coordinated fashion to provide the best available results. At present, no medication is approved by the Food and Drug Administration for the indication of cocaine addiction. Recently, however, five different medications, already approved for other purposes, have been found to be effective among cocaine addicts. Despite clinical trials that show benefit, anticraving medications are not well known and are underused by clinicians. Addiction is a heterogeneous condition, with variability in reactivity to the drug of abuse and to the medications available to treat it. Recent developments in pharmacogenetics may result in improved selection of medications based on genotype.

Alcoholism↗
PubMed2004

A pilot trial of topiramate for the treatment of cocaine dependence.

BACKGROUND: Both GABAergic and glutamatergic neurons appear to be important modulators of the brain reward system and medications that affect GABA and glutamatergic neurotransmission may reduce the rewarding properties of cocaine and reduce cocaine craving. Topiramate, an anticonvulsant, raises cerebral GABA levels, facilitates GABAergic neurotransmission and inhibits glutametergic activity at AMPA/kainite receptors. Thus, it may be useful for treating cocaine dependence. METHODS: The efficacy of topiramate for cocaine dependence was tested in a 13-week, double-blind, placebo-controlled pilot trial (n = 40). Topiramate was titrated gradually over 8 weeks to a dose of 200 mg daily. The primary outcome measure was cocaine abstinence verified by twice weekly urine benzoylecgonine tests (UBT). RESULTS: Eighty-two percent of subjects completed the trial. Analysis of the UBT using a GEE model showed that after week 8, when the dose titration was completed, topiramate-treated subjects were more likely to be abstinent from cocaine compared to placebo-treated subjects (Z = 2.67, P = 0.01). Topiramate-treated subjects were also more likely to attain 3 weeks of continuous abstinence from cocaine (chi2 = 3.9, d.f. = 1, P = 0.05). CONCLUSION: Topiramate may be effective for the treatment of cocaine dependence.

Adolescent↗
PubMed2004

Naltrexone for heroin dependence treatment in St. Petersburg, Russia.

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study we randomized 52 consenting patients who completed detoxification in St. Petersburg to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p<0.05). Since heroin dependence is the main way HIV is being spread in Russia, naltrexone is likely to improve treatment outcome and help reduce the spread of HIV if it can be made more widely available.

Adult↗
PubMed2004

Retrospective study: influence of menstrual cycle on cue-induced cigarette craving.

Cigarettes acquire reinforcing properties from nicotine and from cues associated with their intake. However, smoking in males and females may be reinforced differentially. Smoking in females is posited to be influenced more by cues whereas male smoking is influenced predominantly by the direct pharmacological actions of nicotine in the brain. Menstrual cycle phase may contribute to some of the sex differences observed in smokers. We hypothesized that females may report more intense craving to smoking cue exposure than males and, further, that female craving scores may be influenced by menstrual cycle phase. Thus, we reexamined previously collected cue exposure data with respect to sex and cycle phase. Self-report measures were collected from subjects prior to and immediately following exposure to visual smoking stimuli. The study included 69 male and 41 female treatment-seeking subjects who smoked more than 15 cigarettes per day for more than 10 years. Females were grouped according to cycle phase. Of the female subjects, 17 were classified as follicular phase females (FFemales) and 24 were classified as luteal phase females (LFemales). Change scores were calculated from the subjective data collected before and after stimulus presentation. Contrary to our hypothesis, overall, males and all females did not differ in their level of cue-induced craving; however, when females were separated into groups by cycle phase, FFemales reported significantly less craving than either males or LFemales (p<.05). The suppressed craving response in FFemales suggests an influence of cycle phase on cue-induced craving.

Cues↗
PubMed2003

A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients.

This study examined the association between two specific polymorphisms of the gene encoding the mu-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A(+118)G (Asn40Asp) and C(+17)T (Ala6Val) SNPs in the gene encoding the mu-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p=0.044) and a longer time to return to heavy drinking (p=0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p=0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a mu-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.

Adult↗
PubMed2003

A pilot trial of olanzapine for the treatment of cocaine dependence.

BACKGROUND: Multiple lines of evidence suggest both dopaminergic and serotonergic involvement in the reinforcing effects of cocaine. Medications such as olanzapine, which block dopamine D2 receptors, as well as serotonin receptors 5HT2A and 5HT2C may be able to reduce cocaine use in cocaine dependent patients by reducing the euphoric effects of cocaine and attenuating cocaine craving. METHODS: This was a 12-week, double blind, placebo controlled, pilot trial involving 30 cocaine dependent subjects. Subjects received either olanzapine (10 mg/day) or identical placebo. Outcome measures included treatment retention, qualitative urine benzoylecgonine tests, cocaine craving, clinical global impression scores, and results from the addiction severity index. RESULTS: Treatment retention was slightly, but significantly, better in the placebo-treated subjects. Placebo-treated subjects were more likely to be abstinent from cocaine during the trial compared to olanzapine-treated subjects, based on urine benzoylecgonine results. Olanzapine was not superior to placebo in any outcome measure. CONCLUSIONS: The results of this trial do not support the usefulness of olanzapine for the treatment of cocaine dependence. In fact, olanzapine may worsen cocaine treatment outcome.

Adolescent↗
PubMed2003

Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study.

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. Cocaine withdrawal symptoms are associated with poor clinical outcome and are likely to be reversed by modafinil. In addition, the neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. Our results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Furthermore, pretreatment with modafinil did not intensify cocaine euphoria or cocaine-induced craving. In fact, cocaine euphoria was significantly blunted (P=0.02) in one of our subjective measures.

Adult↗