Personalized Medicine of Alcohol Addiction: Pharmacogenomics and Beyond.

Alcohol addiction or alcoholism is the most severe form of problem drinking. A variety of treatment methods for alcoholism are currently available that combine medications, behavioral treatment and peer support. The drugs that are currently approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence are disulfiram, naltrexone and acamprosate. For many patients, however, these treatments are not effective. Evidence from a number of studies suggests that various factors, both psychosocial and economic, as well as genetic variation, are significant contributors to interindividual variation both of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss different aspects of personalized medicine of alcohol addiction. We focus on pharmacogenomics and beyond, to include the genetics and epigenetics of alcohol addiction as well as other psychosocial and even economic factors that may affect response to alcohol addiction pharmacotherapy. It is anticipated that, within the next 5-10 years, personalized medicine of alcohol addiction will be a reality and it will help reduce the burden of alcoholism from society and increase the well-being and productivity of individuals addicted to alcohol.

Topiramate in Alcohol Use Disorders: Review and Update.

To date, a limited number of pharmacological agents exist to treat alcohol use disorders (AUDs), and there is growing interest in new therapeutic tools. In this framework, topiramate may represent a useful treatment option, although its use is not yet approved for AUDs. The main focus of this review is to discuss all the existing data supporting the use of topiramate in AUDs, with an emphasis on the most recent and relevant clinical implications. In addition, the profile of the alcoholic patient who may benefit more from the use of topiramate is outlined. In this regard, the authors conducted a PubMed search of clinical human studies published in English using the following key words: topiramate alcohol dependence, topiramate alcohol withdrawal and topiramate alcoholism. The evidence suggests that topiramate could be an effective treatment option for the management of AUDs, while there are limited results for its use to treat alcohol withdrawal syndrome. In particular, topiramate shows a greater beneficial effect in subjects with a typology of craving characterised by drinking obsessions and automaticity of drinking. Topiramate, within the dosage range of 75-300 mg/day, could be considered as a first-line treatment option for the management of AUDs. Its use appears to be safe and well-tolerated, especially in light of very recent findings.

The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study.

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular Pressure in Rabbit Models.

PURPOSE: We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-ß-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models. METHODS: Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. ΔIOP and ΔNO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively. RESULTS: Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of ΔIOP or ΔNO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops. CONCLUSIONS: The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC-based drug delivery system promotes drug effectiveness and effective time.

The development of acamprosate as a treatment against alcohol relapse.

INTRODUCTION: Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism. AREAS COVERED: Herein, the authors review the preclinical studies which have assessed the efficacy of acamprosate in various animal models of alcohol dependence and discuss the disparate findings from the major clinical trials. Moreover, the authors discuss the major limitations of these preclinical and clinical studies and offer explanations for the often-contradictory findings. The article also looks at the importance of the calcium moiety that accompanies the salt form of acamprosate and its relevance to its activity. EXPERT OPINION: The recent discovery that large doses of calcium largely duplicate the effects of acamprosate in animal models has introduced a serious challenge to the widely held functional association between this drug and the glutamate neurotransmission system. Future research on acamprosate or newer pharmacotherapeutics should consider assessing plasma and/or brain levels of calcium as a correlate or mediating factor in anti-relapse efficacy. Further, preclinical research on acamprosate has thus far lacked animal models of chemical dependence on alcohol, and the testing of rodents with histories of alcohol intoxication and withdrawal is suggested.

Multiday administration of ivermectin is effective in reducing alcohol intake in mice at doses shown to be safe in humans.

Ivermectin (IVM), an FDA approved anthelmintic agent, can significantly reduce ethanol intake in mice following acute administration. The current study evaluates the sustainability and safety of multiday IVM administration in reducing 10% v/v ethyl alcohol (10E) intake in mice at a dose shown to be safe in humans. We tested the effect of 10-day administration of IVM (3.0 mg/kg/day; intraperitoneally) on reducing 10E intake in C57BL/6J mice using a 24-h, two-bottle choice paradigm. On the 10th day of IVM administration, mice were sacrificed at 0, 0.5, 2, 8, 32, 48, and 72 h after injection. Brain tissue and plasma samples were collected and analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Analysis of variance (ANOVA) was used to assess the effect of 10-day IVM administration on 10E intake, 10E preference, water intake, and total fluid intake with Dunnett's multiple comparison post-hoc test. Individual Student's t-tests were also used to further quantify changes in these dependent variables. IVM significantly decreased 10E intake over a 9-day period (P<0.01). Pre-IVM 10E intake was 9.1±3.2 g/kg/24 h. Following the 9th day of IVM injections, intake dropped by almost 30% (P<0.05). IVM had no effect on total water intake or mouse weight throughout the study; however, there was a significant decrease in both preference for 10E (P<0.01) and total fluid intake (P<0.05). Multiday administration of IVM significantly reduces 10E intake and preference in animals without causing any apparent adverse effects at a dose shown to be safe in humans.

Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice.

RATIONALE: A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents. OBJECTIVE: The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA). METHODS: Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control. RESULTS: In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h. CONCLUSIONS: These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration.

Cigarette smoking predicts differential benefit from naltrexone for alcohol dependence.

BACKGROUND: Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. METHODS: We examined the association between cigarette smoking and drinking outcomes in the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) study, a randomized, double-blind placebo-controlled 16-week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management, combined behavioral therapy) in 1383 alcohol-dependent individuals. RESULTS: Smokers (i.e., more than one half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received combined behavioral intervention or medical management and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking, and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. CONCLUSIONS: These results suggest that naltrexone might be particularly beneficial for improving alcohol use outcomes in alcohol-dependent smokers.

Effects of oral loperamide on efficacy of naltrexone, baclofen and AM-251 in blocking ethanol self-administration in rats.

Naltrexone is a µ-opioid receptor antagonist that has been extensively studied for its ability to block the rewarding effects of ethanol. Opioid receptors are widely distributed within the gastrointestinal tract (GIT). Typically, naltrexone is administered by parenteral routes in nonclinical studies. We initially tested if opioid receptors within the GIT would influence the ability of oral naltrexone to inhibit ethanol oral self-administration in rats using the co-administration of oral loperamide, a peripherally restricted opioid agonist. As expected, oral naltrexone only had modest effects on ethanol intake, and the response was not dose-dependent. However in rats, treatment with loperamide prior to the administration of naltrexone resulted in a suppression of ethanol intake which approached that observed with naltrexone given by the subcutaneous (SC) route. Importantly, administration of loperamide prior to administration of naltrexone did not alter blood concentrations of naltrexone. We then evaluated if oral loperamide would enhance effects of baclofen (a GABA(B) receptor agonist) and AM-251 (a CB-1 receptor antagonist) and found that pre-treatment with loperamide did potentiate the action of both drugs to reduce ethanol self-administration. Finally, the specific opioid receptor type involved was investigated using selective µ- and κ-receptor antagonists to determine if these would affect the ability of the AM-251 and loperamide combination to block ethanol drinking behavior. The effect of loperamide was blocked by ALKS 37, a peripherally restricted µ-receptor antagonist. These data suggest an important role for opioid receptors within the GIT in modulating central reward pathways and may provide new insights into strategies for treating reward disorders, including drug dependency.

[Disulfiram and addiction: reminders and new perspectives of use]. / Le disulfirame (Esperal(®)) dans le traitement des addictions : rappels et nouvelles perspectives d'utilisation.

Disulfiram is a relatively old molecule, which today remains marginal in the treatment of alcoholics diseases. Using this type of treatment is the subject of ethical debate. The prescription of this therapeutic requires clinical and biological rigorous evaluations before treatment. Its main action in treatment of alcoholism is related to the restraint of acetaldehyde dehydrogenase action causing the antabuse reaction. Prescription of disulfiram, supported by specialized programs of compartmental integrated care, brings significant benefit for alcoholic patients. Recently, following the discovery of its action on dopamine metabolism, disulfiram has been a renewed interest in the treatment of addictions to cocaine and pathological gambling. Although current data are insufficient to generalize its use in routine practice, they constitute a line of research interest for the future.

LC-MS/MS method for the determination of carbamathione in human plasma.

Liquid chromatography-tandem mass spectrometry methodology is described for the determination of S-(N,N-diethylcarbamoyl)glutathione (carbamathione) in human plasma samples. Sample preparation consisted of a straightforward perchloric acid medicated protein precipitation, with the resulting supernatant containing the carbamathione (recovery ~98%). For optimized chromatography/mass spec detection a carbamathione analog, S-(N,N-di-i-propylcarbamoyl)glutathione, was synthesized and used as the internal standard. Carbamathione was found to be stable over the pH 1-8 region over the timeframe necessary for the various operations of the analytical method. Separation was accomplished via reversed-phase gradient elution chromatography with analyte elution and re-equilibration accomplished within 8 min. Calibration was established and validated over the concentration range of 0.5-50 nM, which is adequate to support clinical investigations. Intra- and inter-day accuracy and precision determined and found to be <4% and <10%, respectively. The methodology was utilized to demonstrate the carbamathione plasma-time profile of a human volunteer dosed with disulfiram (250 mg/d). Interestingly, an unknown but apparently related metabolite was observed with each human plasma sample analyzed.

Acamprosate determinations in plasma and cerebrospinal fluid after multiple dosing measured by liquid chromatography-mass spectroscopy: a pharmacokinetic study in healthy volunteers.

The central nervous system-active medication acamprosate has been shown to modulate alcohol-related behavior in both preclinical and clinical studies. Although commonly used in the treatment of alcohol dependence, there are still unanswered questions concerning the pharmacokinetic properties of acamprosate. The aims of the present study were to 1) to validate liquid chromatography-mass spectrometry as a method to study the presence of acamprosate in plasma and cerebrospinal fluid (CSF) in humans; and 2) validate previous results on clinically important pharmacokinetic data for acamprosate. In an open label, single-site design, 13 healthy males and females were recruited to 22 days of oral acamprosate treatment (1998 mg/day). Subjects provided in all 256 plasma samples for analysis at regular intervals at Day 1, 7, 14, and 22 of treatment. On Day 22, subjects also left a sample of CSF for measurement of acamprosate. The results showed that steady-state level of acamprosate was accomplished within 5 days after the start of treatment and remained fairly stable for 2 to 3 days after termination of treatment. Variations in plasma concentrations corresponded to earlier studies and did not exceed those for comparable pharmacotherapeutic agents. Acamprosate concentrations in the CSF were below the limit of quantification, ie, estimated concentrations between 9 and 33 ng/mL. Plasma concentrations were more than 25 times higher than in lumbar CSF. The low CSF levels seen after 3 weeks of treatment may provide an explanation to the delay in therapeutic effect noticed in treatment studies on acamprosate. A longer duration of treatment might be necessary to obtain clinically significant brain levels of acamprosate. In summary, the present study validated liquid chromatography-mass spectrometry as a method for assessment of compliance to acamprosate treatment. Furthermore, the results suggest that the mechanism of action of acamprosate needs to be further explored with regard to the peripheral actions of the drug.

The neurobiology, clinical efficacy and safety of acamprosate in the treatment of alcohol dependence.

IMPORTANCE TO THE FIELD: Acamprosate, marketed under the brand name Campral, (Forest Pharmaceuticals, Inc., Saint Louis, MO, USA; Merck Sante s.a.s., Lyon, France) is an orally administered drug approved in the US and throughout much of the world for treating alcohol dependence. Its safety and efficacy have been demonstrated in a number of clinical trials worldwide and as with all pharmacotherapies for alcoholism, it is used in conjunction with psychosocial interventions. AREAS COVERED IN THIS REVIEW: This article reviews the mechanism of action, clinical efficacy and safety of acamprosate in Phase I, II and III randomized controlled trials involving healthy and alcohol-dependent populations using published reports from 1984 to 2009. WHAT THE READER WILL GAIN: This review provides an update of the mechanism of action and the safety and efficacy profile of acamprosate. TAKE HOME MESSAGE: Acamprosate appears to act centrally to restore the normal activity of glutamatergic neurotransmission altered by chronic alcohol exposure. Acamprosate's excellent safety profile along with several pharmacokinetic and pharmacodynamic characteristics make it well suited for treating a broad population of alcohol-dependent patients.

Delayed and prolonged coma after acute disulfiram overdose.

We report the case of a 35-year-old man presenting with a delayed and prolonged coma due to an intentional overdose with disulfiram without simultaneous alcohol ingestion. The clinical features--comprising a severe toxic encephalopathy with coma and convulsions, in combination with a quadriparesis outlasting the loss of consciousness--are summarized, and the physiopathology is reviewed.

Fatal lactic acidosis precipitated by nifedipine in a patient treated with disulfiram and antiretrovirals.

A 43 year old man with HIV and HCV infection and liver cirrhosis developed fatal lactic acidosis within five days from starting nifedipine for arterial hypertension. Multiple drug interactions, current and accumulated drug toxicities and the reduced liver function, might in combination have led to the acute lactic acidosis.

Review of topiramate: an antiepileptic for the treatment of alcohol dependence.

Despite the availability of currently approved medications and various psychosocial therapies, alcohol abuse and dependence are increasingly prevalent in the United States, and carry a significant socioeconomic burden. Recently, the novel anti-epileptic topiramate has shown great promise as a new treatment for this disorder. The objective of this review is to discuss the limitations of the currently available options for treating alcohol dependence, to review the results of clinical trials assessing the efficacy of topiramate in treating alcohol dependence, and to describe the pharmacological characteristics and mechanisms of action of topiramate as related to this indication. We systematically reviewed Medline, EMBASE, Cochran Reviews and PsycINFO search terms included combinations of the terms "pharmacotherapy" "topiramate", "alcoholism" and "alcohol dependence." Searches were last updated 24 October 2008. Currently approved treatments include disulfiram, naltrexone tablets and injection, and acamprosate. Of these, naltrexone has shown the most benefit, however the effect size is small and may reach its most promising potential when combined with medical management. Alternatively, through multiple mechanisms of action, topiramate in clinical trials has demonstrated safety and efficacy in decreasing both craving and withdrawal symptoms and increasing quality of life measures among alcohol-dependent individuals. The findings of this review suggest that topiramate is a promising new option for the treatment of alcohol dependence, and may offer substantial benefits over currently approved medications. While the manufacturer will not pursue approval of an indication for the treatment of alcohol dependence, the drug will soon be available generically, making it more affordable for a greater proportion of the public.

Pharmacokinetics of acamprosate calcium in healthy Chinese subjects after oral administration of three dosage levels.

To study the pharmacokinetics of acamprosate calcium (CAS 77337-73-6) in healthy Chinese subjects after oral administration of three dosage levels, 12 healthy subjects were divided into three groups and given a single oral dose of 333 or 666 or 1332 mg acamprosate calcium (enteric coated tablet). A sensitive liquid chromatography-tandem mass spectrometry method (LC-MS-MS) was used for the determination of acamprosate calcium in plasma. Both, a non-compartmental and compartmental method were used for analysis of kinetics parameters. The main pharmacokinetic parameters of the 333, 666 and 1322 mg regimen groups were as follows: tmax 7.5 +/- 2.6 h, 7.4 +/- 2.2 h, 8.1 +/- 3.1 h, Cmax 134.8 +/- 103.9 ng/mL, 297.5 +/- 188.1 ng/mL, 385.4 +/- 155.7 ng/mL, t1/2 13.3 +/- 11.4 h, 17.9 +/- 18.1 h, 15.1 +/- 9.1 h, AUC(0-t) 1772 +/- 1323 ng x h/mL, 3709 +/- 1195 ng x h/mL, 6421 +/- 2486 ng x h/mL, respectively. Statistical analysis of AUC/D showed that AUCs increased linearly with the administered dose. The kinetic process of acamprosate calcium was best fitted to a one-compartment model.

[Recent results in relaps prevention of alcoholism with Disulfiram]. / Aktueller Stand der pharmakotherapeutischen Rückfallprophylaxe mit Disulfiram.

OBJECTIVE: For more than 50 years, disulfiram has been approved for the treatment of chronic alcohol dependence. In the last years there has been observed an increase in the prescription of disulfiram in germany. It acts as a psychological deterrence of a possible disulfiram-alcohol reaction. This paper describes the current clinical impact and possible future of disulfiram. METHODS: Clinical trials using disulfiram for the treatment of alcohol dependence were discussed. Furthermore, the options of combining disulfiram with novel anti-craving agents were considered. Moreover, experiences and results of a cross section of the Mannheimer Disulfiram program will be presented. RESULTS AND CONCLUSIONS: Nowadays there exists consent in the matter that Disulfiram should only be adminsitered as part of a comprehensive therapy program, this means in the context of an intake under medical supervision. This paper is supposed to help estimate the value of disulfiram in recent addiction medicine.

Analysis of acamprosate in beagle dog plasma by LC-MS-MS.

A rapid, sensitive, and specific analytical method was developed and validated to quantify acamprosate calcium in beagle dog plasma. The method employs a single plasma protein precipitation, and the analytes are separated by chromatography on an Acquity UPLC HSS T3 column and analyzed by mass spectrometry in the multiple reaction monitoring (MRM) mode. The method has a chromatographic run time of 1.25 min and a linear calibration curve over the range 200-10000 ng/mL (r(2)>0.9994). The intra-day and inter-day accuracy and precision were within 10.0% for the analyte. Acamprosate was stable during all sample storage, preparation, and analytical periods. This method was employed in a pharmacokinetic study of an acamprosate 333 mg enteric-coated tablet in 8 male beagle dogs that received single 666 mg doses (333 mg x 2 tablets). The proposed method enables identification and quantification in pharmacokinetic studies of acamprosate in beagle dog plasma.