The clinical utility of the Medication Adherence Questionnaire (MAQ) in an alcohol pharmacotherapy trial.

BACKGROUND: Medication nonadherence is a ubiquitous problem in pharmacology treatment for alcohol use disorders. Unintentional and purposeful nonadherence as measured by the Medication Adherence Questionnaire (MAQ) has been shown to predict problems with medication adherence; however, feedback from the MAQ has never been incorporated into a behavioral intervention to facilitate medication adherence. We assessed the integration of the MAQ into medical management (MM), a counseling approach frequently employed in conjunction with alcohol pharmacotherapy, to determine whether prior patterns of nonadherence could be addressed effectively to promote medication adherence. METHODS: We conducted a post-hoc analysis of data from 131 alcohol dependent smokers who participated in a double blind, placebo controlled study of varenicline for the treatment of alcohol dependence. At baseline, participants completed a single administration of the MAQ, which asks 2 questions about unintentional nonadherence (e.g., forgetting) and 2 questions about purposeful nonadherence (e.g., stopping because feeling good or feeling bad). Based on these responses, participants were divided into 1 of 3 three categories. Adherent (n=60), Unintentional or Purposeful Nonadherent (n=50) and Unintentional and Purposeful Nonadherent (n=21). Over the course of the 16-week treatment period, patients were expected to participate in 12 medical management (MM) sessions; a brief psychosocial treatment. Feedback based on the MAQ responses was integrated into the MM sessions to facilitate medication and treatment adherence. RESULTS: The 3 adherence groups were compared on baseline characteristics, medication adherence, treatment attendance and end-of-treatment patient ratings of treatment helpfulness. Baseline demographics and characteristics were not significantly different among the three categories. We found no statistically significant differences among the three groups with respect to pill adherence, treatment attendance, and treatment satisfaction ratings. CONCLUSIONS: The findings suggest that the incorporation of MAQ feedback into the MM approach could be effective in mitigating risks associated with prior patterns of nonadherence suggesting that further testing of the integrated behavioral approach is warranted.

In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

Gender-related differences in the characteristics of problem gamblers using a gambling helpline.

OBJECTIVE: The characteristics of male and female gamblers utilizing a gambling helpline were examined to identify gender-related differences. METHOD: The authors performed logistic regression analyses on data obtained in 1998-1999 from callers to a gambling helpline serving southern New England. RESULTS: Of the 562 phone calls used in the analyses, 349 (62.1%) were from male callers and 213 (37.9%) from female callers. Gender-related differences were observed in reported patterns of gambling, gambling-related problems, borrowing and indebtedness, legal problems, suicidality, and treatment for mental health and gambling problems. Male gamblers were more likely than female gamblers to report problems with strategic or "face-to-face" forms of gambling, e.g., blackjack or poker. Female gamblers were more likely to report problems with nonstrategic, less interpersonally interactive forms of gambling, e.g., slot machines or bingo. Female gamblers were more likely to report receiving nongambling-related mental health treatment. Male gamblers were more likely to report a drug problem or an arrest related to gambling. High rates of debt and psychiatric symptoms related to gambling, including anxiety and depression, were observed in both groups. CONCLUSIONS: Individuals with gambling disorders have gender-related differences in underlying motivations to gamble and in problems generated by excessive gambling. Different strategies may be necessary to maximize treatment efficacy for men and for women with gambling problems.

Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.

OBJECTIVE: To assess the feasibility and efficacy of two interventions for improving adherence to antiretroviral therapy regimens in HIV-infected subjects compared with a control intervention. DESIGN: Randomized, controlled, pilot study. SETTING: Department of Veterans Affairs HIV clinic and community-based HIV clinical trials site. PARTICIPANTS: Fifty-five HIV-infected subjects on stable antiretroviral therapy regimens. Subjects were predominantly male (89%) and African American (69%), and had histories of heroin or cocaine use (80%). INTERVENTIONS: Four weekly sessions of either nondirective inquiries about adherence (control group, C), cue-dose training, which consisted of the use of personalized cues for remembering particular dose times, and feedback about medication taking using Medication Event Monitoring System (MEMS) pill bottle caps, which record time of bottle opening (CD group), or cue-dose training combined with cash reinforcement for correctly timed bottle opening (CD+CR). MEASUREMENTS: Opening of the pill bottle within 2 hours before or after a predetermined time was measured by MEMS. RESULTS: Adherence to the medication as documented by MEMS was significantly enhanced during the 4-week training period in the CD+CR group, but not in the CD group, compared with the control group. Improvement was also seen in adherence to antiretroviral drugs that were not the object of training and reinforcement. Eight weeks after training and reinforcement were discontinued, adherence in the cash-reinforced group returned to near-baseline levels. CONCLUSIONS: Cue-dose training with cash reinforcement led to transient improvement in adherence to antiretroviral therapy in a population including mostly African Americans and subjects with histories of drug abuse. However, we were not able to detect any sustained improvement beyond the active training period, and questions concerning the timing and duration of such an intervention require further study. Randomized, controlled clinical studies with objective measures of adherence can be conducted in HIV-infected subjects and should be employed for further evaluation of this and other adherence interventions.

In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist.

L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(¿3-[4-(2-pyridin yl)-1-piperidinyl]propyl¿amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.

Psychological stress, drug-related cues and cocaine craving.

RATIONALE: While several environmental situations may produce cocaine craving, there is little research on whether patterns of drug cue reactivity are similar across different environmental situations. OBJECTIVE: This study examined whether two different environmental situations, psychological stress and drug cues, produce similar or varying patterns of cue reactivity in 20 cocaine dependent individuals. METHODS: All subjects participated in a single laboratory session and were exposed to stress, drug cues and neutral-relaxing imagery conditions. Cocaine and alcohol craving, emotion state ratings, subjective anxiety, heart rate and salivary cortisol measures were assessed. RESULTS: Significant increases in cocaine and alcohol craving were observed with stress and drug cues imagery but not with neutral-relaxing imagery. In addition, stress and drug cues situations produced similar increases in subjective anxiety, heart rate and salivary cortisol levels. Significant increases in negative emotion ratings and decreases in positive emotion ratings were found for stress and drug cues conditions as compared to the neutral condition. CONCLUSIONS: The findings indicate that a similar and comparable pattern of cue reactivity is induced by stress and drug cue manipulations. Furthermore, the comparable increases in subjective anxiety and negative affect observed with stress-induced and drug cue-induced craving provides support for the negative reinforcement model of drug craving and relapse. The negative affectivity co-occurring with the craving state appears to be an important target in the development of new treatments for cocaine dependence.

Preparation and evaluation of 1,3-diaminocyclopentane-linked dihydropyrimidinone derivatives as selective alpha1a-receptor antagonists.

Several 1,3-diaminocyclopentane linked alpha1a-receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their effect on alpha1-receptor binding.

Alcohol and eating disorders: implications for alcohol treatment and health services research.

BACKGROUND: This paper focuses on the co-occurrence of alcoholism and eating disorders and the clinical implications for treating this comorbidity in women with alcohol use disorders. There is substantial literature that supports higher than expected rates of co-occurrence of these two disorders. In addition, there is evidence that the co-occurrence of alcoholism and eating disorders is more likely to occur in the presence of other psychiatric disorders. A critical analysis of the studies on the comorbidity of these disorders is conducted along with a review of the possible etiologic association between the two disorders. Crucial questions related to pharmacological and behavioral treatments for this subgroup of alcoholic women with eating disorders are raised from a health services research perspective. CONCLUSIONS: There is substantial evidence that alcoholism and eating disorders co-occur at high rates. However, as this review points out, several important research questions remain regarding both the clinical manifestations of each problem in women who are comorbid for both disorders and the treatment implications.

Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.

A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.

In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

Motivational interviewing with psychiatrically ill substance abusing patients.

This pilot study reports the relative efficacy of a one-session preadmission motivational interview (n = 13) compared to a standard preadmission interview (n = 10) for psychiatrically ill substance abusing patients in a partial hospital program.

Multidimensional subtypes and treatment outcome in first-time DWI offenders.

The concurrent and predictive validity of Type A and B alcoholism subtypes was evaluated in 246 first-time driving-while-intoxicated (DWI) offenders. K-means analysis indicated that a two-cluster solution was optimal with Type Bs (28%) exhibiting greater premorbid risk factors, alcohol and psychosocial severity, drinking consequences, psychopathology, higher stage of change, and less coping confidence in comparison to less severe Type As (72%). After baseline assessment, participants were randomly assigned to one of three 10-week group treatments (DWI Education, Coping Skills, Interactional), and reassessed at termination, and at 6-month and 1-year follow-ups. Type B was associated with more severe symptoms after treatment, but there was no evidence for patient-treatment matching effects. Although Type A/B may be an important theoretical model for guiding alcoholism research, it usefulness and efficiency for treatment matching, planning, or placement purposes is questioned.

Naltrexone-induced nausea in patients treated for alcohol dependence: clinical predictors and evidence for opioid-mediated effects.

Naltrexone, an opiate antagonist, is well tolerated by most alcoholic patients; however, a subset reports significant nausea that can limit the effectiveness of this therapy. The goal of this study was to identify risk factors for naltrexone-precipitated nausea to assist in the development of management strategies to maximize the overall effectiveness of naltrexone. On the basis of the hypothesis that alterations in the endogenous opioid system occur with repeated stimulation of endogenous opioids by alcohol, the authors predicted that the recency and intensity of alcohol use would be related to the risk of naltrexone-induced nausea. One hundred twenty alcohol-dependent subjects participated in an open-label trial of naltrexone. After 5 to 30 days of abstinence, subjects received an initial naltrexone dose of 25 mg followed by a dose of 50 mg daily thereafter for 10 weeks. New-onset adverse effects were rated mild, moderate, or severe after 1 week of naltrexone. Logistic regression analyses were used to predict moderate to severe nausea during the first week of therapy from pretreatment patient characteristics. Moderate to severe nausea was reported by 18 subjects (15%) and was linked to poorer medication compliance and heavier drinking during treatment. Risk of nausea was significantly predicted by age, gender, intensity of drinking, duration of abstinence, and the interaction of abstinence duration and intensity of drinking. At shorter durations of abstinence, lighter drinkers were more likely to experience nausea than heavier drinkers. However, the risk of nausea declined with longer periods of abstinence, particularly for lighter drinkers. Younger age and female gender were associated with higher rates of nausea. These results support the hypothesis that recency and intensity of alcohol use are related to opiate antagonist-precipitated nausea and suggest that long-term alcohol use may result in alterations in the endogenous opioid system. Potential strategies to minimize the risk of nausea in vulnerable individuals are discussed.

Effects of alcohol on baseline startle and prepulse inhibition in young men at risk for alcoholism and/or anxiety disorders.

OBJECTIVE: This study examined the hypothesis that a decreased reaction to alcohol and a deficit in prepulse inhibition (PPI) of the startle reflex are characteristics of male offspring of alcoholics without comorbid anxiety disorder. METHOD: Male offspring (N = 51) with a parental history of (1) alcoholism only, (2) anxiety disorder only, (3) alcoholism and anxiety disorder, and (4) no psychiatric disorder participated in an experiment examining the effects of alcohol on the acoustic startle reflex and on PPI. The experiment was carried out in two sessions in which subjects received an alcoholic beverage and placebo beverage on alternate days. RESULTS: The magnitude of startle was reduced by alcohol in each group. However, the degree of reduction was less in the offspring of alcoholics only compared to the other groups. In addition, PPI was reduced in the offspring of alcoholics only compared to the offspring of parents with no psychiatric disorder. CONCLUSIONS: A reduced reactivity to the effect of alcohol and a deficit in PPI might constitute vulnerability markers for alcoholism, but only in offspring of alcoholics without comorbid anxiety disorder.

Illegal behaviors in problem gambling: analysis of data from a gambling helpline.

Problem gambling behaviors, particularly the most severe form, which is pathological gambling (PG), represent an emerging public health problem. Compared with the general population, individuals with problem gambling are more likely to have reports of legal issues, including commission of crimes, arrest, and incarceration. The goal of the present study is to examine the characteristics of individuals seeking help for gambling problems with regard to reports of illegal behavior secondary to gambling. Individuals with gambling problems were identified through use of a 24-hour gambling helpline, and information regarding the identified problem gambler was investigated with respect to reported presence or absence of gambling-related illegal behaviors. Identified gamblers with reported gambling-related illegal behaviors compared with those without such behaviors appeared to experience more severe gambling-related problems. Despite being on average younger, gamblers with acknowledged gambling-related illegal behaviors were more likely to have reports of having problems with multiple forms of gambling, debts to acquaintances, been suicidal secondary to gambling, used alcohol or drugs excessively, and received mental health treatment. Secondary analyses of the subgroup of gamblers with gambling-related illegal behaviors revealed that those with reports of arrest or incarceration secondary to gambling compared with those with gambling-related illegal behaviors but without arrest or incarceration secondary to gambling were more likely to have features similar to those described for individuals with antisocial personality disorder (ASPD). That is, the gambler with reported arrest or incarceration secondary to gambling was more likely to be male, unemployed, single, and have reports of problems with excessive drug or alcohol use. In contrast, the gamblers acknowledging gambling-related illegal behaviors but not arrest or incarceration secondary to gambling were predominantly female and more likely to have reports of problems with non-strategic forms of gambling (e.g., slot machine), owing money to legitimate sources of borrowing, having filed for bankruptcy, and having family problems related to gambling. The findings indicate: (1) individuals with reported legal problems secondary to gambling represent a more ill subpopulation of problem gamblers; and (2) there exist separate subgroups of gamblers with gambling-related illegal behaviors (i.e., those with or without reported arrest or incarceration secondary to gambling) with strikingly different characteristics and possibly different treatment needs. The results of the present study highlight the importance of the identification and treatment of individuals with gambling problems with respect to legal issues.

Design and synthesis of novel dihydropyridine alpha-1a antagonists.

A series of analogs of SNAP 5150 containing heteroatoms at C2 or C6 positions is described. Herein, we report that the presence of alkyl substituted heteroatoms at the C2(6)-positions of the dihydropyridine are well tolerated. In addition, 15 inhibited the phenylephrine induced contraction of dog prostate tissue with a Kb of 1.5 nM and showed a Kb (DBP, dogs, microg/kg)/Kb (IUP, dogs, microg/kg) ratio of 14.8/2.5.